Pharmaceutical compositions and methods for use

ABSTRACT

Pharmaceutical compositions aryl substituted amine compounds, and in particular, 3-aminophenyl amine compounds are provided. Representative compounds are (E)-4-(3-aminophenyl)-3-buten-1-amine, (E)-N-methyl-4-(3-aminophenyl)-3-buten-1-amine and (E)-N-methyl-5-(3-aminophenyl)-4-penten-2-amine.

This application is a Divisional of Ser. No. 09/177,231 filed Oct. 22,1998.

BACKGROUND OF THE INVENTION

The present invention relates to pharmaceutical compositions, andparticularly pharmaceutical compositions incorporating compounds thatare capable of affecting nicotinic cholinergic receptors. Moreparticularly, the present invention relates to compounds capable ofactivating nicotinic cholinergic receptors, for example, as agonists ofspecific nicotinic receptor subtypes. The present invention also relatesto methods for treating a wide variety of conditions and disorders, andparticularly conditions and disorders associated with dysfunction of thecentral and autonomic nervous systems.

Nicotine has been proposed to have a number of pharmacological effects.See, for example, Pullan et al. N. Engl. J. Med. 330:811-815 (1994).Certain of those effects may be related to effects upon neurotransmitterrelease. See for example, Sjak-shie et al., Brain Res. 624:295 (1993),where neuroprotective effects of nicotine are proposed. Release ofacetylcholine and dopamine by neurons upon administration of nicotinehas been reported by Rowell et al., J. Neurochem. 43:1593 (1984); Rapieret al., J. Neurochem. 50:1123 (1988); Sandor et al., Brain Res. 567:313(1991) and Vizi, Br. J. Pharmacol. 47:765 (1973). Release ofnorepinephrine by neurons upon administration of nicotine has beenreported by Hall et al., Biochem. Pharmacol. 21:1829 (1972). Release ofserotonin by neurons upon administration of nicotine has been reportedby Hery et al., Arch. Int. Pharmacodyn. Ther. 296:91 (1977). Release ofglutamate by neurons upon administration of nicotine has been reportedby Toth et al., Neurochem Res. 17:265 (1992). In addition, nicotinereportedly potentiates the pharmacological behavior of certainpharmaceutical compositions used for the treatment of certain disorders.See, Sanberg et al., Pharmacol. Biochem. & Behavior 46:303 (1993);Harsing et al., J. Neurochem. 59:48 (1993) and Hughes, Proceedings fromIntl. Symp. Nic. S40 (1994). Furthermore, various other beneficialpharmacological effects of nicotine have been proposed. See, Decina etal., Biol. Psychiatry 28:502 (1990); Wagner et al., Pharmacopsychiatry21:301 (1988); Pomerleau et al., Addictive Behaviors 9:265 (1984);Onaivi et al., Life Sci. 54(3):193 (1994); Tripathi et al., JPET 221:91-96 (1982) and Hamon, Trends in Pharmacol. Res. 15:36.

Various nicotinic compounds have been reported as being useful fortreating a wide variety of conditions and disorders. See, for example,those types of conditions and disorders set forth in Williams et al.DN&P 7(4):205-227 (1994), Arneric et al., CNS Drug Rev. 1(1):1-26(1995), Arneric et al., Exp. Opin. Invest. Drugs 5(1): 79-100 (1996),Bencherif et al., JPET 279:1413-1421 (1996), Lippiello et al., JPET279:1422-1429 (1996), Damaj et al., Neuroscience (1997), Holladay etal., J. Med. Chem 40(28): 4169-4194 (1997), Bannon et al., Science 279:77-80 (1998), PCT WO 94/08992, PCT WO 96/31475, PCT WO 97/19059,European Patent Application 857,725, and U.S. Pat. Nos. 5,278,176 toLin, 5,583,140 to Bencherif et al., 5,597,919 to Dull et al., 5,604,231to Smith et al.,5,616,716 to Dull et al. and 5,811,442 to Bencherif etal.

Nicotinic compounds are reported as being particularly useful fortreating a wide variety of Central Nervous System (CNS) disorders. CNSdisorders are a type of neurological disorder. CNS disorders can be druginduced; can be attributed to genetic predisposition, infection ortrauma; or can be of unknown etiology. CNS disorders compriseneuropsychiatric disorders, neurological diseases and mental illnesses;and include neurodegenerative diseases, behavioral disorders, cognitivedisorders and cognitive affective disorders. There are several CNSdisorders whose clinical manifestations have been attributed to CNSdysfunction (i.e., disorders resulting from inappropriate levels ofneurotransmitter release, inappropriate properties of neurotransmitterreceptors, and/or inappropriate interaction between neurotransmittersand neurotransmitter receptors). Several CNS disorders can be attributedto a cholinergic deficiency, a dopaminergic deficiency, an adrenergicdeficiency and/or a serotonergic deficiency. CNS disorders of relativelycommon occurrence include presenile dementia (early onset Alzheimer'sdisease), senile dementia (dementia of the Alzheimer's type),Parkinsonism including Parkinson's disease, anxiolysis, attentiondeficit hyperactivity disorder, depression, dyslexia, epilepsy,Huntington's chorea, hyperkinesia, mania, neuro-endocrine disorders,schizophrenia, sleep disorders, tardive dyskinesia, Tourette's syndrome,and dysregulation of food intake.

It would be desirable to provide a useful method for the prevention andtreatment of a condition or disorder by administering a nicotiniccompound to a patient susceptible to or suffering from such a conditionor disorder. It would be highly beneficial to provide individualssuffering from certain disorders (e.g., CNS disorders) with interruptionof the symptoms of those disorders by the administration of apharmaceutical composition containing an active ingredient havingnicotinic pharmacology and which has a beneficial effect (e.g., upon thefunctioning of the CNS), but which does not provide any significantassociated side effects. It would be highly desirable to provide apharmaceutical composition incorporating a compound which interacts withnicotinic receptors, such as those which have the potential to affectthe functioning of the CNS, but which compound when employed in anamount sufficient to affect the functioning of the CNS, does notsignificantly affect those receptor subtypes which have the potential toinduce undesirable side effects (e.g., appreciable activity at skeletalmuscle and ganglia sites).

SUMMARY OF THE INVENTION

The present invention relates to aryl substituted amine compounds, andin particular, 3-aminophenyl amine compounds. Representative compoundsare (E)-4-(3-aminophenyl)-3-buten-1-amine,(E)-N-methyl-4-(3-aminophenyl)-3-buten-1-amine,(E)-N-methyl-5-(3-aminophenyl)-4-penten-2-amine,2-((3-aminophenyl)methoxy)ethan-1-amine,1-((3-aminophenyl)methoxy)propan-2-amine andN-methyl-1-((3-aminophenyl)methoxy)propan-2-amine. The present inventionalso relates to methods for synthesizing certain aryl substituted aminecompounds, such as the compounds of the present invention. The presentinvention also relates to prodrug derivatives of aryl substituted aminecompounds of the present invention.

Compounds of the present invention exhibit activity at acetylcholinereceptors, and are useful towards modulating release of ligands involvedin neurotransmission. Compounds of the present invention are selectiveto certain nicotinic acetylcholine receptor subtypes, and can act asagonists at those receptor subtypes. Hence, the present inventionrelates to methods for modulating the activity of certain nicotinicacetylcholine receptor subtypes by administering a compound of thepresent invention.

The present invention also relates to methods for the prevention ortreatment of a wide variety of conditions or disorders, and particularlythose disorders characterized by dysfunction of nicotinic cholinergicneurotransmission including disorders involving neuromodulation ofneurotransmitter release, such as dopamine release. The presentinvention also relates to methods for the prevention or treatment ofdisorders, such as central nervous system (CNS) disorders, which arecharacterized by an alteration in normal neurotransmitter release. Thepresent invention also relates to methods for the treatment of certainconditions (e.g., a method for alleviating pain). The methods involveadministering to a subject an effective amount of a compound of thepresent invention. The present invention also relates to methods for thetreatment of Alzheimer's disease comprising coadministering certain arylsubstituted amine compounds, such as the compounds of the presentinvention, with a cholinesterase inhibitor such as tacrine or donepezil.

The present invention, in another aspect, relates to a pharmaceuticalcomposition comprising an effective amount of a compound of the presentinvention. Such a pharmaceutical composition incorporates a compoundwhich, when employed in effective amounts, has the capability ofinteracting with relevant nicotinic receptor sites of a subject, andhence has the capability of acting as a therapeutic agent in theprevention or treatment of a wide variety of conditions and disorders,particularly those disorders characterized by an alteration in normalneurotransmitter release. Preferred pharmaceutical compositionscomprise'compounds of the present invention.

The pharmaceutical compositions of the present invention are useful forthe prevention and treatment of disorders, such as CNS disorders, whichare characterized by an alteration in normal neurotransmitter release.The pharmaceutical compositions provide therapeutic benefit toindividuals suffering from such disorders and exhibiting clinicalmanifestations of such disorders in that the compounds within thosecompositions, when employed in effective amounts, have the potential to(i) exhibit nicotinic pharmacology and affect relevant nicotinicreceptor sites (e.g., act as pharmacological agonists to activatenicotinic receptors), and (ii) elicit neurotransmitter secretion, andhence prevent and suppress the symptoms associated with those diseases.In addition, the compounds are expected to have the potential to (i)increase the number of nicotinic cholinergic receptors of the brain ofthe patient, (ii) exhibit neuroprotective effects and (iii) whenemployed in effective amounts do not cause appreciable adverse sideeffects (e.g., significant increases in blood pressure and heart rate,significant negative effects upon the gastrointestinal tract, andsignificant effects upon skeletal muscle). The pharmaceuticalcompositions of the present invention are believed to be safe andeffective with regards to prevention and treatment of a wide variety ofconditions and disorders.

The foregoing and other aspects of the present invention are explainedin detail in the detailed description and examples set forth below.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention include compounds of the formula:

where A, A^(I), A^(II), A^(III) and A^(IV) are substituent speciescharacterized as having a sigma m value greater than 0, often greaterthan 0.1, and generally greater than 0.2, and even greater than 0.3;less than 0 and generally less than −0.1; or 0; as determined inaccordance with Hansch et al., Chem. Rev. 91:165 (1991). Preferably,each substituent species has a sigma m value which is between about −0.3and about 0.75, and frequently is between about −0.25 and about 0.6, andindividual substituent species can have a sigma m value of 0; B′ is asubstituted or unsubstituted two atom bridging species wherein at leastone atom is carbon bonded to the benzene ring and the other atom iscarbon, oxygen, nitrogen or sulfur; as such, B′, can be

(e.g., alkyl-containing, olefinic or acetylinic linkage, unsubstitutedor substituted) with X being oxygen, nitrogen or sulfur, and R′ and R″being straight chain or branched alkyl (or R′ and R″ and the interveningatoms can combine to form a ring structure, such as cyclopropylcyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl orquinuclidinyl), with at least one of each of R′ and R″ being hydrogenpreferred, and R′ being hydrogen being especially preferred) and can bepart of a substituted or unsubstituted cycloalkyl ring (e.g.,cyclopropyl, cyclobutyl, cyclopentyl,); B′, A^(I) and the associatedcarbon atoms can combine to form a ring structure (e.g., a 5 or 6membered ring); B′ and E and the intervening atoms can combine to form aring structure (e.g., cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl); n is an integer from 0 to 5, preferably 1, 2or 3, more preferably 1 or 2, and most preferably 1; E, E^(I), E^(II)and E^(III) individually represent hydrogen, alkyl (e.g., straight chainor branched alkyl including C₁-C₈, preferably C₁-C₅, such as methyl,ethyl, or isopropyl), substituted alkyl, halo substituted alkyl (e.g.,straight chain or branched alkyl including C₁-C₈, preferably C₁-C₅, suchas trifluoromethyl or trichloromethyl), cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, alkylaryl, substituted alkylaryl, arylalkyl or substitutedarylalkyl; all of E, E^(I), E^(II), E^(III) can be hydrogen, or at leastone of E, E^(I), E^(II), E^(III) is non-hydrogen (e.g., alkyl,substituted alkyl, halo substituted alkyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, alkylaryl, substituted alkylaryl, arylalkyl or substitutedarylalkyl) and the remaining E, E^(I), E^(II), E^(III) are hydrogen;either E and E^(I) or E^(II) and E^(III) and their associated carbonatom can combine to form a ring structure such as cyclopentyl,cyclohexyl or cycloheptyl; either E and E^(II) or E^(I) and E^(III) andtheir associated carbon atoms can combine to form a ring structure suchas cyclopentyl, cyclohexyl or cycloheptyl; Z and Z^(I) individuallyrepresent hydrogen, alkyl (e.g., straight chain or branched alkylincluding C₁-C₈, preferably C₁-C₅, such as methyl, ethyl, or isopropyl),substituted alkyl, acyl, alkoxycarbonyl, or aryloxycarbonyl andpreferably at least one of Z and Z^(I) is hydrogen, and most preferablyZ is hydrogen and Z^(I) is methyl; alternatively Z is hydrogen and Z^(I)represents a ring structure (cycloalkyl, heterocyclyl or aryl), such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl, quinuclidinyl, pyridinyl, quinolinyl, pyrimidinyl, phenyl,benzyl, thiazolyl or oxazolyl (where any of the foregoing can besuitably substituted with at least one substituent group, such as alkyl,alkoxyl, halo, or amino substituents); alternatively Z is hydrogen andZ^(I) is propargyl; alternatively Z, Z^(I), and the associated nitrogenatom can form a ring structure such as aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, morpholinyl, 2-imino-2,3-dihydrothiazolyl or2-imino-2,3-dihydrooxazolyl, and in certain situations, piperazinyl(e.g., piperazine); Z^(I) and E^(I) and the associated carbon andnitrogen atoms can combine to form a monocyclic ring structure such asazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl orisoxazolaminyl; however it is preferred that when Z^(I) and E^(I) andthe associated carbon and nitrogen atoms combine to form such a ring,neither E^(I) nor E^(III) are substituted or unsubstituted aryl,heteroaryl, benzhydryl or benzyl; Z^(I) and E^(III) and the associatedcarbon and nitrogen atoms can combine to form a monocyclic ringstructure such as azetidinyl, pyrrolidinyl, piperidinyl, or piperazinylor a bicyclic ring structure such as 3-(2-azabicyclo[4.2.0]octyl),3-(2-azabicyclo[2.2.2]octyl), or 3-(2-azabicyclo[2.2.1]heptyl); Z, Z^(I)and E^(III) and the associated carbon and nitrogen atoms can combine toform a bicyclic ring structure such as quinuclidinyl,2-(1-azabicyclo[2.2.1]-heptyl), or 2-(1-azabicyclo[3.3.0]octyl), or atricyclic ring structure such as azaadamantyl; Z^(I), E^(II) and E^(III)and the associated carbon and nitrogen atoms can combine to form abicyclic ring structure such as 1-(2-azabicyclo[2.2.1]heptyl); Z, Z^(I),E^(II) and E^(III) and the associated carbon and nitrogen atoms cancombine to form a tricyclic ring structure. More specifically, A, A^(I),A^(II), A^(III) and A^(IV) include H, alkyl, substituted alkyl, alkenyl,substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substitutedalkylaryl, arylalkyl, substituted arylalkyl, F, Cl, Br, I, NR′R″, CF₃,OH, CN, NO₂, C₂R′, SH, SCH₃, N₃, SO₂CH₃, OR′, (CR′R″)_(q)OR′,O—(CR′R″)_(q)C₂R′, SR′, C(═O)NR′R″, NR′C(═O)R″, C(═O)R′,(CR′R″)_(q)C₂R′, C(═O)OR′, OC(═O)R′, OC(═O)NR′R″ and NR′C(═O)OR″ where qis an integer from 1 to 6 and R′ and R″ are individually hydrogen oralkyl (e.g., C₁-C₁₀ alkyl, preferably C₁-C₅ alkyl, and more preferablymethyl, ethyl, isopropyl or isobutyl), cycloalkyl (e.g., cyclopropylcyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl), anon-aromatic heterocyclic ring wherein the heteroatom of theheterocyclic moiety is separated from any other nitrogen, oxygen orsulfur atom by at least two carbon atoms (e.g., quinuclidinyl,pyrrolidinyl, and piperidinyl), an aromatic group-containing species(e.g., pyridyl, quinolinyl, pyrimidinyl, furanyl, phenyl, and benzylwhere any of the foregoing can be suitably substituted with at least onesubstituent group, such as alkyl, alkoxyl, halo, or amino substituents).Other representative aromatic ring systems are set forth in Gibson etal., J. Med. Chem. 39:4065 (1996). Typically, A^(IV) includes NR′R″, OR′and NO₂ where R′ and R″ are as defined above. Preferably, A^(IV) is NH₂,NHCH₃ or N(CH₃)₂, with NH₂ being most preferred. Adjacent substituentsA, A^(I), A^(II), A^(III) and A^(IV) can combine to form one or moresaturated or unsaturated, substituted or unsubstituted carbocyclic orheterocyclic rings containing, but not limited to, ether, acetal, ketal,amine, ketone, lactone, lactam, carbamate, or urea functionalities. Inaddition, it is highly preferred that A is hydrogen and it is preferredthat A^(I) is hydrogen. Preferably, E, E^(I) and E^(II) are hydrogen. Inone preferred embodiment, n is 1 or 2, E, E^(I) and E^(II) each arehydrogen, and E^(III) is alkyl (e.g., methyl). In another preferredembodiment, n is 1 or 2 and E, E^(I), E^(II), E^(III) each are hydrogen.Depending upon the identity and positioning of each individual E, E^(I),E^(II) and E^(III), certain compounds can be optically active.Additionally, compounds of the present invention can have chiral centerswithin the side chain (e.g., the compound can have an R or Sconfiguration). Depending upon E, E^(I), E^(II) and E^(III), compoundsof the present invention have chiral centers, and the present inventionrelates to racemic mixtures of such compounds as well as singleenantiomers. Typically, the selection of n, E, E^(I), E^(II) and E^(III)is such that up to about 4, and frequently up to 3, and usually 0, 1 or2, of the substituents designated as E, E^(I), E^(II) and E^(III) arenon-hydrogen substituents (i.e., substituents such as alkyl orhalo-substituted alkyl). Typically, it is preferred that A^(II) is H, Bror OR′, where R′ preferably is methyl, ethyl, isopropyl, isobutyl ortertiary butyl.

As employed herein, “alkyl” refers to straight chain or branched alkylradicals including C₁-C₈, preferably C₁-C₅, such as methyl, ethyl, orisopropyl; “substituted alkyl” refers to alkyl radicals further bearingone or more substituent groups such as hydroxy, alkoxy, mercapto, aryl,heterocyclo, halo, amino, carboxyl, carbamyl, cyano, and the like;“alkenyl” refers to straight chain or branched hydrocarbon radicalsincluding C₁-C₈, preferably C₁-C₅ and having at least one carbon-carbondouble bond; “substituted alkenyl” refers to alkenyl radicals furtherbearing one or more substituent groups as defined above; “cycloalkyl”refers to saturated or unsaturated cyclic ring-containing radicalscontaining three to eight carbon atoms, preferably three to six carbonatoms; “substituted cycloalkyl” refers to cycloalkyl radicals furtherbearing one or more substituent groups as defined above; “aryl” refersto aromatic radicals having six to ten carbon atoms; “substituted aryl”refers to aryl radicals further bearing one or more substituent groupsas defined above; “alkylaryl” refers to alkyl-substituted aryl radicals;“substituted alkylaryl” refers to alkylaryl radicals further bearing oneor more substituent groups as defined above; “arylalkyl” refers toaryl-substituted alkyl radicals; “substituted arylalkyl” refers toarylalkyl radicals further bearing one or more substituent groups asdefined above; “heterocyclyl” refers to saturated or unsaturated cyclicradicals containing one or more heteroatoms (e.g., O, N, S) as part ofthe ring structure and having two to seven carbon atoms in the ring;“substituted heterocyclyl” refers to heterocyclyl radicals furtherbearing one or more substituent groups as defined above; “acyl” refersto straight chain or branched alkyl- or substituted alkyl-carbonylradicals including C₁-C₈, preferably C₁-C₅, such as formyl, acetyl, orpropanoyl; “alkoxycarbonyl” refers to an alkyl or substituted alkylradical attached to an O-carbonyl moiety; and “aryloxycarbonyl” refersto an aryl or substituted aryl radical attached to an O-carbonyl moiety.

Of particular interest are compounds of the formula:

where A^(IV) is NR′R″, OR′ and NO₂, A, A^(I), A^(II), A^(III), E, E^(I),E^(II), E^(III), R′, R″, Z and Z^(I) are as defined hereinbefore andwhere the wavy line in the structure indicates that the compound canhave the cis (Z) or trans (E) form. Preferably, A^(IV) is NH₂, NHCH₂ orN(CH₃)₂, with NH₂ being most preferred. Typically, the compound has thetrans (E) form, R′ and R″ both are hydrogen, E, E^(I) and E^(II) eachare hydrogen, E^(III) is hydrogen or lower alkyl, Z is hydrogen ormethyl, and Z^(I) is hydrogen.

Also of particular interest are compounds of the formula:

where A^(IV) is NR′R″, OR′ and NO₂ and A, A^(I), A^(II), A^(III), E,E^(I), E^(II), E^(III), R′, R″, Z and Z^(I) are as defined hereinbefore.Preferably, A^(IV) is NH₂, NHCH₃ or N(CH₃)₂, with NH₂ being mostpreferred. Typically, R′ is hydrogen, E, E^(I) and E^(II) each arehydrogen, E^(III) is hydrogen or lower alkyl, Z is hydrogen or methyl,and Z^(I) is hydrogen.

The methods by which compounds of the present invention can besynthetically produced can vary. Certain aryl substituted olefinic aminecompounds can be prepared using a palladium catalyzed coupling reactionof an aromatic halide and a terminal olefin containing a protected aminesubstituent (e.g., phthaloyl, benzoyl, or tert-butoxycarbonyl protectinggroups), removal of the protective group to obtain a primary amine, andoptional alkylation to provide a secondary or tertiary amine. Inparticular, certain compounds, such as(E)-4-(3-aminophenyl)-3-buten-1-amine can be prepared by subjecting a3-halo-substituted aniline compound such as 3-bromoaniline or3-iodoaniline (commercially available from Aldrich Chemical Company andLancaster Synthesis, Inc.) to a palladium catalyzed Heck couplingreaction using an olefin possessing a protected amine functionality(e.g., such an olefin provided by the reaction of a phthalimide saltwith 4-halo-1-butene), followed by removal of the phthaloyl protectinggroup with methylamine or hydrazine. Typically, the types of proceduresset forth in W. C. Frank et al., J. Org. Chem. 43: 2947 (1978) and N. J.Malek et al., J. Org. Chem. 47: 5395 (1982) involving apalladium-catalyzed coupling of an olefin and an aromatic halide areused. In a similar manner, other compounds can be prepared by the Heckreaction of 3-halo-substituted aniline compounds with an olefincontaining a protected amine functionality, (such as provided by thereaction of a phthalimide salt with 3-halo-1-propene, 5-halo-1-penteneor 6-halo-1-hexene), followed by removal of the phthaloyl protectinggroup with methylamine or hydrazine. Primary amines, produced in theseprocedures, may be alkylated by sequential reaction with di-tert-butyldicarbonate (to give the N-tert-butoxycarbonyl derivatives), andfollowed by reaction with sodium hydride and an alkyl halide (e.g.,methyl iodide, benzyl bromide, propargyl bromide) inN,N-dimethylformamide, as described by Dull in U.S. Pat. No. 5,597,919.Removal of the tert-butoxycarbonyl group with trifluoroacetic acid willgive the secondary amine (i.e., the corresponding N-methyl, N-benzyl, orN-propargyl derivative).

In a similar approach, other compounds such as(E)-N-methyl-4-(3-aminophenyl)-3-buten-1-amine can be prepared bysubjecting a 3-halo-substituted aniline such as 3-bromoaniline or3-iodoaniline to a palladium catalyzed coupling reaction with an olefinpossessing a protected amine functionality (e.g., such asN-methyl-N-(3-buten-1-yl)benzamide), followed by removal of the benzoylprotecting group with aqueous acid. The required olefin can be preparedby reacting 4-bromo-1-butene with an excess of condensed methylamine inN,N-dimethylformamide in the presence of potassium carbonate to giveN-methyl-3-buten-1-amine. Treatment of the latter compound with benzoylchloride in dichloromethane containing triethylamine affords theolefinic side chain, N-methyl-N-(3-buten-1-yl) benzamide.

In another approach, other compounds such as(E)-N-methyl-4-(3-aminophenyl)-3-buten-1-amine can be prepared bysubjecting a 3-halo-substituted aniline such as 3-bromoaniline or3-iodoaniline to a palladium catalyzed coupling reaction with an olefinpossessing a protected amine functionality (e.g., such asN-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine), followed by removalof the tert-butoxycarbonyl protecting group with trifluoroacetic acid.The required olefin, N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-aminecan be prepared by reacting 4-bromo-1-butene with an excess of condensedmethylamine in N,N-dimethylformamide in the presence of potassiumcarbonate to give N-methyl-3-buten-1-amine. The latter compound can betreated with one equivalent of di-tert-butyldicarbonate intetrahydrofuran to giveN-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine.

The manner in which certain aryl substituted olefinic amine compoundspossessing a branched side chain, such as(E)-N-methyl-5-(3-aminophenyl)-4-penten-2-amine, are provided can vary.By using one synthetic approach, the compound can be synthesized in aconvergent manner, in which the side chain,N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine is coupled with a3-halo-substituted aniline, such as 3-bromoaniline (N-protected with thephthaloyl group), under Heck reaction conditions, followed by removal ofthe tert-butoxycarbonyl protecting group with trifluoroacetic acid andthen removal of the phthaloyl protecting group with methylamine. Therequired olefin, N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine canbe prepared by treatment of commercially available 4-penten-2-ol(Aldrich Chemical Company, Lancaster Synthesis Inc) withp-toluenesulfonyl chloride in pyridine to afford 4-penten-2-olp-toluenesulfonate, previously described by T. Michel, et al., LiebigsAnn. 11:1811 (1996). The resulting tosylate can be converted toN-methyl-4-penten-2-amine by heating with excess methylamine. The latteramine, previously mentioned by A. Viola et al., J. Chem. Soc., Chem.Commun. (21): 1429 (1984), can be converted to the olefinic amine sidechain, N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine by treatmentwith di-tert-butyl dicarbonate in dry tetrahydrofuran.

The aniline nitrogen can also be alkylated using the coupling method ofO. Mitsunobu, Synthesis: 1 (1981). Any primary or secondary alcohol,including those containing other functional groups, may be used in thecoupling. As an example, reaction of 3-bromoaniline with 3-quinuclidinol(Aldrich Chemical Company) in the presence of triphenylphosphine anddiethyl azodicarboxylate will result in the formation of3-bromo-N-(3-quinuclidinyl)aniline, which can be used in Heck couplingsas described above.

Using the previously described synthetic methods involving the Heckreaction, certain N-alkyl-3-aminophenyl substituted olefinic aminecompounds such as(E)-N-methyl-4-(N-methyl-3-aminophenyl)-4-buten-1-amine can be preparedstarting from 3-halo-N-alkylanilines such as 3-iodo-N-methyl-aniline.The latter compound can be prepared from commercially available3-iodoaniline (Aldrich Chemical Company, Lancaster Synthesis, Inc.)using the techniques of S. Padmanabhan et al., Synth. Commun. 27:691-699(1997). 3-Iodoaniline can be monomethylated using trimethyl orthoformatein the presence of concentrated sulfuric acid followed by acidhydrolysis to give 3-iodo-N-methyl-aniline. CertainN,N-dialkyl-3-aminophenyl substituted olefinic amine compounds such as(E)-N-methyl-4-(N,N-dimethyl-3-aminophenyl)-4-buten-1-amine can beprepared starting from 3-bromo-N,N-dimethyl-aniline, which iscommercially available from Karl Industries and Lancaster Synthesis,Inc.

Alternatively, an olefinic alcohol, such as 3-buten-1-ol, can becondensed with an aromatic halide, such as 3-bromoaniline or3-iodoaniline. Protection of the nitrogen functionality of the anilinecompound can be provided by a phthaloyl protecting group, using phthalicanhydride. Typically, the types of procedures set forth in Frank et al.,J. Org. Chem. 43: 2947-2949 (1978) and Malek et al., J. Org. Chem. 47:5395-5397 (1982) involving a palladium-catalyzed coupling of an olefinand an aromatic halide are used. The olefinic alcohol optionally can beprotected as a tert-butyldimethylsilyl ether prior to the coupling.Desilylation then produces the olefinic alcohol. The alcoholcondensation product then is converted to an amine using the type ofprocedures set forth in deCosta et al., J. Org. Chem., 35: 4334-4343(1992). Typically, the alcohol condensation product is converted to thearyl substituted olefinic amine by activation of the alcohol usingmethanesulfonyl chloride or p-toluenesulfonyl chloride, followed bymesylate or tosylate displacement using ammonia, or a primary orsecondary amine. Thus, when the amine is ammonia, an aryl substitutedolefinic primary amine compound is provided; when the amine is a primaryamine such as methylamine or cyclobutylamine, an aryl substitutedolefinic secondary amine compound is provided; and when the amine is asecondary amine such as dimethylamine or pyrrolidine, an arylsubstituted olefinic tertiary amine compound is provided. Otherrepresentative olefinic alcohols include 4-penten-1-ol, 5-hexen-2-ol,5-hexen-3-ol, 3-methyl-3-buten-1-ol, 2-methyl-3-buten-1-ol,4-methyl-4-penten-1-ol, 4-methyl-4-penten-2-ol, 1-octen-4-ol,5-methyl-1-hepten-4-ol, 4-methyl-5-hexen-2-ol, 5-methyl-5-hexen-2-ol,5-hexen-2-ol and 5-methyl-5-hexen-3-ol. Trifluoromethyl-substitutedolefinic alcohols, such as 1,1,1-trifluoro-4-penten-2-ol, can beprepared from 1-ethoxy-2,2,2-trifluoro-ethanol and allyltrimethylsilaneusing the procedures of Kubota et al., Tetrahedron Lett. 33(10):1351-1354 (1992), or from trifluoroacetic acid ethyl ester andallyltributylstannane using the procedures of Ishihara et al.,Tetrahedron Lett. 34(56): 5777-5780 (1993). Certain olefinic alcoholsare optically active, and can be used as enantiomeric mixtures or aspure enantiomers in order to provide the corresponding optically activeforms of aryl substituted olefinic amine compounds. When an olefinicallylic alcohol, such as methallyl alcohol, is reacted with an aromatichalide, an aryl substituted olefinic aldehyde is produced; and theresulting aldehyde can be converted to an aryl substituted olefinicamine compound by reductive amination (e.g., by treatment using an alkylamine and sodium cyanoborohydride). Typically, substituent groups ofsuch 3-halo-aniline-type compounds are such that those groups cansurvive contact with those chemicals (e.g., tosyl chloride andmethylamine) and the reaction conditions experienced during thepreparation of the aryl substituted olefinic amine compound.Alternatively, substituents such as —OH, —NH₂ and —SH can be protectedas corresponding acyl compounds, or substituents such as —NH₂ can beprotected as a phthalimide functionality.

Certain 5-alkoxy-3-aminophenyl substituted olefinic amine compounds ofthe present invention such as(E)-N-methyl-5-(5-methoxy-3-aminophenyl)-4-penten-2-amine, can besynthesized by coupling a 3-halo-5-alkoxyaniline such as3-bromo-5-methoxyaniline or 3-iodo-5-methoxyaniline (protected by aphthaloyl functionality) with an olefin containing a secondary alcoholfunctionality, 4-penten-2-ol, under Heck reaction conditions. Theresulting secondary alcohol intermediate can be converted to itsp-toluenesulfonate ester, followed by treatment with methylamine (whichalso removes the protecting group). Alternatively, certain5-alkoxy-3-aminophenyl substituted olefinic amine compounds can besynthesized by coupling a 3-halo-5-alkoxyaniline such as3-bromo-5-methoxyaniline or 3-iodo-5-methoxyaniline (protected by aphthaloyl functionality) with an olefinic side chain compound, such asN-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine, followed by removalof the protecting groups. The required 3-halo-5-alkoxyaniline compoundssuch as 3-bromo-5-methoxyaniline and 3-iodo-5-methoxyaniline can beprepared using the techniques of T. A. Emokpae et al., J. Chem. Soc.,Perkin Trans 2 (1):14-17 (1977) and B. Liedholm, Acta Chem. Scand., Ser.B 38:877-884(1984). In the former method, 3-bromo-5-methoxyaniline and3-iodo-5-methoxyaniline can be prepared starting from commerciallyavailable 1,3,5-trinitrobenzene. Treatment of the latter compound withrefluxing sodium methoxide produces 3,5-dinitroanisole. One of the nitrogroups is then reduced to give 3-methoxy-5-nitroaniline. The lattercompound can be diazotized and treated with copper(I) bromide to give1-bromo-3-methoxy-5-nitrobenzene. Reduction with tin and hydrochloricacid gives 3-bromo-5-methoxyaniline. In a similar manner,3-iodo-5-methoxyaniline can be prepared by diazotizing3-methoxy-5-nitroaniline to give 1-iodo-3-methoxy-5-nitrobenzene. Thelatter compound can be reduced with iron filings and hydrochloric acidto give 3-iodo-5-methoxyaniline. Other 3-halo-5-alkoxyanilines such as3-bromo-5-ethoxyaniline, 3-bromo-5-isopropoxyaniline, and3-bromo-5-sec-butoxyaniline can be prepared using similar techniques. Assuch, compounds of the present invention such as(E)-N-methyl-5-(5-ethoxy-3-aminophenyl)-4-penten-2-amine,(E)-N-methyl-5-(5-isopropoxy-3-aminophenyl)-4-penten-2-amine, and(E)-N-methyl-5-(5-sec-butoxy-3-aminophenyl)-4-penten-2-amine can besimilarly prepared.

The manner in which optically active forms of certain aryl substitutedolefinic amine compounds, such as(2S)-(4E)-N-methyl-5-(3-aminophenyl)-4-penten-2-amine, are provided canvary. In one synthetic approach, such compounds can be synthesized bycoupling a halo-substituted aniline, 3-bromoaniline (which is protectedwith an appropriate protecting group, such as a phthaloyl group), withan olefin possessing a chiral, secondary alcohol functionality,(2R)-4-penten-2-ol, under Heck reaction conditions(acetonitriletriethylamine (1:1, v/v) using a catalyst consisting of 1mole % palladium(II) acetate and 4 mole % tri-o-tolylphosphine). Theresulting chiral alcohol intermediate,(2R)-(4E)-5-(N-phthaloyl-3-aminophenyl)-4-penten-2-ol can be convertedto its corresponding p-toluenesulfonate ester, which can be subsequentlytreated with excess methylamine, resulting in tosylate displacement withinversion of configuration to give the chiral amine,(2S)-(4E)-N-methyl-5-(3-aminophenyl)-4-penten-2-amine. Typically, thetypes of procedures set forth in W. C. Frank et al., J. Org. Chem. 43:2947 (1978) and N. J. Malek et al., J. Org. Chem. 47: 5395 (1982)involving a palladium-catalyzed coupling of an aromatic halide and anolefin are used. The chiral side chain, (2R)-4-penten-2-ol can beprepared by treatment of the chiral epoxide, (R)-(+)-propylene oxide(commercially available from Fluka Chemical Company) with vinylmagnesiumbromide in tetrahydrofuran at low temperatures (−25 to −10° C.) usingthe general synthetic methodology of Kalivretenos et al., J. Org. Chem.56: 2883 (1991), to afford (2R)-4-penten-2-ol.

In a similar manner, the corresponding aryl substituted olefinic amineenantiomer, such as(2R)-(4E)-N-methyl-5-(3-aminophenyl)-4-penten-2-amine, can besynthesized by the Heck coupling of 3-bromoaniline and(2S)-4-penten-2-ol. The resulting intermediate,(2S)-(4E)-5-(3-aminophenyl)-4-penten-2-ol, can be converted to itsp-toluenesulfonate, which is subjected to methylamine displacement. Thechiral alcohol, (2S)-4-penten-2-ol, can be prepared from(S)-(−)-propylene oxide (commercially available from Aldrich ChemicalCompany) using a procedure analogous to that described for thepreparation of (2R)-4-penten-2-ol from (R)-(+)-propylene oxide asreported by Kalivretenos et al., J. Org. Chem. 56: 2883 (1991).

Certain aryl substituted olefinic amine compounds of the presentinvention can be prepared by coupling an N-protected, modified aminioacid residue, such as 4-(N-methyl-N-tert-butyloxycarbonyl)aminobutyricacid methyl ester, with an aryl lithium compound, as can be derived froma suitable aryl halide and an alkyl lithium such as butyl lithium. Theresulting N-protected aryl ketone is then chemically reduced to thecorresponding alcohol, converted to the alkyl halide, mesylate ortosylate, and subsequently dehydrohalogenated or otherwise eliminated tointroduce the olefin functionality. Removal of the N-protecting groupthen affords the desired compound.

Alternatively, the aryl substituted olefinic amine compounds of thepresent invention can be prepared by coupling an N-protectedaminoaldehyde, such as 4-(N-methyl-N-(tert-butoxycarbonyl)amino)pentanalwith an aryllithium. The required aldehyde can be prepared accordingprocedure described by Otsuka et al., J. Am Chem. Soc. 112: 838-845(1990), starting from commercially available1,5-dimethyl-2-pyrrolidinone (Aldrich Chemical Company). Thus, heating1,5-dimethyl-2-pyrrolidinone with 6N hydrochloric acid forms4-(methylamino)pentanoic acid, which can be readily esterified to ethyl4-(methylamino)pentanoate. The latter compound can be treated with oneequivalent of di-tert-butyl dicarbonate to give ethyl4-(N-methyl-N-(tert-butoxycarbonyl)amino)pentanoate which is thenreduced with DIBAL-H to give4-(N-methyl-N-(tert-butoxycarbonyl)amino)pentanal. Reaction of thisaldehyde with an aryllithium will generate an alcohol, which cansubsequently be converted to the N-protected olefinic amine by theprocedures mentioned above (conversion of the alcohol to the halide andsubsequent dehydrohalogenation). Removal of the tert-butoxycarbonylprotecting group affords the desired (E)-5-aryl-4-penten-2-amine.Suitably protected 3-haloanilines can be used as precursors of thearyllithiums required for this process, as described by Guijarro et al.,Tetrahedron 49: 469-82 (1992) and by Gross et al., J. Org. Chem. 58,2104-9 (1993). Thus 3-chloroaniline can be treated sequentially withpivaloyl chloride, n-butyllithium, and lithium in the presence ofcatalytic naphthalene to give a pivaloyl protected3-(aminophenyl)lithium. This aryllithium, upon condensation with4-(N-methyl-N-(tert-butoxycarbonyl)amino)pentanal and subsequentconversion of the alcohol into the alkene (as described above) andremoval of the protecting groups, gives(E)-N-methyl-5-(3-aminophenyl)-4-penten-2-amine.

Aryl substituted olefinic amines of the present invention may containazacyclic functionality, such as pyrrolidine or quinuclidine. Themethods of synthesis of such compounds may vary. In one method, a Heckcoupling can be used to attach a vinyl or allyl substituted nitrogenheterocycle to a 3-haloaniline. ThusN-(tert-butoxycarbonyl)-2-allylpyrrolidine and 3-bromoaniline can becoupled under conditions described by W. C. Frank et al., J. Org. Chem.43: 2947 (1978) and N. J. Malek et al., J. Org. Chem. 47: 5395 (1982)involving palladium catalysis. Removal of the protecting group, usingtrifluoroacetic acid, will give2-(1-(3-aminophenyl)propen-3-yl)pyrrolidine. The requisiteN-(tert-butoxycarbonyl)-2-allylpyrrolidine can be made from commerciallyavailable 2-pyrrolidinemethanol (Aldrich Chemical Company). Treatment of2-pyrrolidinemethanol with di-tert-butyl dicarbonate results inprotection of the amine as its tert-butoxycarbonyl derivative.Subsequent reaction with p-toluenesulfonyl chloride in pyridine,followed by sodium iodide in acetone, gives2-(iodomethyl)-N-(tert-butoxycarbonyl)pyrrolidine. This can be coupledwith vinylmagnesium in the presence of cuprous iodide to giveN-(tert-butoxycarbonyl)-2-allylpyrrolidine. The use of enantiomericallypure 2-pyrrolidinemethanol (both R and S isomers are available fromAldrich Chemical Company) results in the production of the singleenantiomer of N-(tert-butoxycarbonyl)-2-allylpyrrolidine.

Likewise, 2-allylquinuclidine can be coupled with 3-bromoaniline, underHeck conditions, to give 2-(1-(3-aminophenyl)propen-3-yl)quinuclidine.The required 2-allylquinuclidine can be produced from 3-quinuclidinone(Aldrich Chemical Company) by alkylation and deoxygenation. Thus,3-quinuclidinone is converted into its isopropylimine withisopropylamine and molecular sieves. Treatment of the imine with lithiumdiisopropylamide and allyl bromide, followed by hydrolysis, gives2-allyl-3-quinuclidinone. Deoxygenation, by conversion of the ketoneinto its p-toluenesulfonylhydrazone and reduction with sodiumborohydride, gives 2-allylquinuclidinone.

There are a number of methods by which the (Z)-olefinic isomers of arylsubstituted olefinic amine compounds can be synthetically produced. Inone approach, the (Z)-isomers of aryl substituted olefinic aminecompounds can be prepared by the controlled hydrogenation of thecorresponding alkynyl compounds (e.g., aN-methyl-5-(3-aminophenyl)-4-butyn-2-amine-type compound) usingcommercially available Lindlar catalyst (Aldrich Chemical Company) usingthe methodology set forth in H. Lindlar et al., Org. Syn. 46: 89 (1966).The requisite alkynyl compounds can be prepared by the palladiumcatalyzed coupling of an aromatic halide, preferably a3-bromoaniline-type or a 3-iodoaniline-type compound with an alkynylside chain compound (e.g., an N-methyl-4-pentyn-2-amine-type compound).Typically the methodology set forth in L. Bleicher et al., Synlett. 1115(1995) is used for the palladium catalyzed coupling of an aryl halidewith a monosubstituted alkyne in the presence of copper(I) iodide andtriphenylphosphine and potassium carbonate as a base. Alkynyl compoundssuch as N-methyl-4-pentyn-2-amine can be prepared from commerciallyavailable 4-pentyn-2-ol (Aldrich Chemical Company) by treatment withp-toluenesulfonyl chloride in pyridine, followed by reaction of theresulting 4-pentyn-2-ol p-toluenesulfonate with excess methylamineeither as a 40% aqueous solution or as a 2.0 M solution intetrahydrofuran. In some instances it may be necessary to protect theamino functionality of the N-methyl-4-pentyn-2-amine-type compound bytreatment with di-tert-butyl dicarbonate to give the tert-butoxycarbonylprotected amine-type compound. Such protected amine compounds mayundergo the palladium catalyzed coupling with aryl halides and thesubsequent controlled hydrogenation of the resulting alkynyl compoundmore easily than the unprotected amine compounds. Thetert-butoxycarbonyl protecting group can be easily removed using astrong acid such as trifluoroacetic acid to yield the (Z)-olefinicisomers of aryl substituted olefinic amine compounds.

The manner in which aryl substituted acetylenic amine compounds of thepresent invention are synthetically produced can vary. For example, anaryl substituted acetylenic amine compound, such as anN-methyl-4-(3,4-dimethoxyphenyl)-3-butyn-1-amine type compound, can beprepared using a number of synthetic steps: (i) conversion of3,4-dimethoxybenzaldehyde to a1,1-dihalo-2-(3,4-dimethoxyphenyl)-ethylene using a carbon tetrahalideand triphenylphosphine, (ii) side chain elaboration of this intermediateby reaction with butyl lithium and ethylene oxide, affording4-(3,4-dimethoxyphenyl)-3-butyn-1-ol, (iii) conversion of thisintermediate to its methanesulfonate ester or p-toluenesulfonate ester,and (iv) mesylate or tosylate displacement with methyl amine, affordingan N-methyl-4-(3,4-dimethoxyphenyl)-3-butyn-1-amine type compound.Representative alkylene oxides which can be employed either in racemicor optically active form include propylene oxide, 1,2-epoxybutane,1,2-epoxypentane, 1,2-epoxyhexane, (E)-2,3-epoxybutane, and(Z)-2,3-epoxybutane. Other substituted benzaldehydes, such as3-methoxybenzaldehyde, can be employed and other substituted aromaticaldehydes can be used. By the controlled hydrogenation of the alkynylcompounds using commercially available Lindlar catalyst using themethodology previously described, the (Z)-isomers of aryl substitutedolefinic amine compounds can be obtained.

Compounds of the present invention, with alkyl or aryl substitution onone or both of the olefinic carbons, can be made by a variety ofmethods. For instance, the Wittig reaction of an alkyl aryl ketone withan (aminoalkyl)triphenylphosphonium ylide will give an aryl substitutedalkenamine. In one illustration of this chemistry,(3-bromopropyl)triphenylphosphonium bromide (Aldrich Chemical Company)can be reacted with a variety of primary and secondary amines to givethe (3-(N-alkylamino)propyl)triphenylphosphonium bromides and(3-(N,N-dialkylamino)propyl)triphenylphosphonium bromides. These can betreated with n-butyllithium to generate the corresponding ylides whichare then reacted with ketones to give substituted alkenamines, asdescribed by Tretter et al. in U.S. Pat. No. 3,354,155 (1967). Thusstepwise treatment of(3-bromopropyl)triphenylphosphonium bromide withmethylamine, n-butyllithium, and phthaloyl protected 3-aminoacetophenone(Aldrich Chemical Company) produces the phthaloyl protectedN-methyl-4-(3-aminophenyl)-3-penten-1-amine. Removal of the phthaloylprotecting group using hydrazine hydrate will produceN-methyl-4-(3-aminophenyl)-3-penten-1-amine. In general, mixtures of Eand Z isomers generated by such Wittig reactions are separable bychromatographic methods.

Another method by which branched olefinic compounds of the presentinvention (i.e., those with alkyl or aryl substitution on one or both ofthe olefinic carbons) can be made is by the reaction of aryllithiumswith various aminoketones, protected when necessary as theirN-tert-butoxycarbonyl derivatives. The required protected aminoketonesare produced from the commercially available haloketones by sequentialprocess involving (i) reaction of a haloketone with ethylene glycol andp-toluenesulfonic acid (to produce the ethylene ketal), (ii) reaction ofthe haloketone ethylene ketal with a primary or secondary amine inN,N-dimethylformamide (to convert the halides into their correspondingsecondary and tertiary amines), (iii) protection of the aminofunctionality by treatment with di-tert-butyl dicarbonate (to convertsecondary amines into their N-tert-butoxycarbonyl derivatives), and (iv)treatment with pyridinium p-toluenesulfonate in acetone (to remove theketal protecting group from the ketone). Alternatively the ethyleneketal can be removed by any of a variety of methods designed to retainother functionality, such as that described by Huet et al., Synthesis 63(1978). Thus, 5-chloro-2-pentanone (Aldrich Chemical Company) andmethylamine can be converted by the above reaction sequence intoN-methyl-N-(tert-butoxycarbonyl)-5-amino-2-pentanone. Subsequentreaction of this protected aminoketone with a lithiated N-protectedaniline, such as those described by Guijarro et al., Tetrahedron 49:469-82 (1992) and by Gross et al., J. Org. Chem. 58: 2104-9 (1993), willafford an alcohol which can be converted to the alkene (mixture of E andZ isomers). Deprotection gives a mixture of E and Z isomers ofN-methyl-4-(3-aminophenyl)-3-penten-1-amine.

The manner in which certain aryl substituted aliphatic amine compoundsof the present invention are synthetically produced can vary.Preparation of various aryl substituted aliphatic amine compounds can becarried out using the types of techniques similar to those disclosed byL. Rondahl, Acta Pharm. Suec. 13: 229-234 (1976). For example, anN-methyl-4-(3-aminophenyl)-3-butan-1-amine type compound can be preparedby the reaction of methylamine with the chloro-intermediate,1-chloro-4-(3-aminophenyl)-butane (or its hydrochloride salt). Thelatter compound can be obtained by treating 4-(3-aminophenyl)-butan-1-olwith thionyl chloride. The aliphatic alcohol,4-(3-aminophenyl)-butan-1-ol can be prepared from the Heck reaction of3-bromoaniline and 3-buten-1-ol, followed by hydrogenation of theolefinic intermediate, 4-(3-aminophenyl)-3-buten-1-ol. In anotherapporach, certain aryl substituted aliphatic amine compounds thatpossess a saturated side chain rather than an unsaturated side chain canbe prepared by hydrogenation of the corresponding aryl substitutedolefinic amine compounds or the corresponding acetylenic precursors.Hydrogenation procedures similar to those described by Kamimura et al.,Agr. Biol. Chem. 27 (10): 684-688 (1963) can be used.

The manner in which certain aryl substituted olefinic amine compounds,such as (E)-N-methyl-5-(3-methoxyphenyl)-4-penten-2-amine, are providedcan vary. By using one synthetic approach, the compound can besynthesized in a convergent manner, in which either 3-bromoanisole or3-iodoanisole (commercially available from Aldrich Chemical Company orLancaster Synthesis, Inc.) is coupled with the previously described sidechain compound, N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine underHeck reaction conditions, followed by removal of the tert-butoxycarbonylprotecting group with a strong acid such as trifluoroacetic acid. In asimilar manner, (E)-N-methyl-4-(3-methoxyphenyl)-3-buten-1-amine can beprepared by the Heck coupling reaction of a 3-halo-anisole with thepreviously mentioned side chain compound,N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine, followed by removal ofthe tert-butoxycarbonyl protecting group with a strong acid such astrifluoroacetic acid.

Certain commercially available fused polycyclic haloaromatics can beused to make the corresponding olefinic amine compounds using thepreviously described Heck reaction. Thus 6-bromoindole, commerciallyavailable from Biosynth Biochemica and Synthetica and protected on thering nitrogen if necessary, can be coupled under palladium catalysiswith 3-buten-1-ol using the procedures set forth in W. C. Frank et al.,J. Org. Chem. 43: 2947 (1978) and N. J. Malek et al., J. Org. Chem. 47:5395 (1982); the resulting alcohol intermediate allowed to react withp-toluenesulfonyl chloride to give the corresponding p-toluenesulfonateester; and the ester treated with methylamine to give(E)-N-methyl-4-(6-indolyl)-3-buten-1-amine. The same compound can beproduced by palladium catalyzed coupling of 6-bromoindole toN-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine (the synthesis of whichis described above) and subsequently removing the tert-butoxycarbonylprotecting group. Alternatively, the 6-bromoindole can be reduced usingdiborane and trifluoroacetic acid in tetrahydrofuran as described by Guet al., Zhongguo Yaowu Huaxue Zazhi 3: 58-9, 64 (1993) to give thecorresponding 6-bromoindoline (6-bromo-2,3-dihydroindole), and theindoline protected as its tert-butoxycarbonyl derivative and used in theHeck coupling. Subsequent transformation as above and removal of theprotecting group will yield(E)-N-methyl-4-(6-indolinyl)-3-buten-1-amine. Certain polycyclic phenolscan also be converted into olefinic amines by first reacting them withtrifluoromethanesulfonic anhydride to give the correspondingtrifluoromethanesulfonate ester and subsequent palladium catalyzedcoupling of the ester with a protected amine, as described by Sonessonet al., J. Org. Chem. 61: 4756 (1996), and further transformation asdescribed above. Thus 8-hydroxyjulolidine, available from AldrichChemical Company, can be converted into(E)-N-methyl-4-(8-julolidinyl)-3-buten-1-amine.

Other polycyclic haloaromatics are available through well-knowntransformations of commercially available materials. Thus1,3-benzodioxole (from Aldrich Chemical Company) can be nitrated to give4-nitro-1,3-benzodioxole using the procedure described by Takakis etal., J. Heterocycl. Chem. 28: 625 (1991). Subsequent bromination, astaught by Dauksas et al., Khim. Geterotsikl. Soedin. Issue 9: 1183(1979) gives 6-bromo-4-nitro-1,3-benzodioxole. Reduction of the nitrogroup to the amine group, accomplished with either tin or iron filingsin hydrochloric acid, provides 4-amino-6-bromo-1,3-benzodioxole whichcan be coupled in a Heck process, as previously described, to give(E)-N-methyl-4-(6-(4-amino-1,3-benzodioxol)yl)-3-buten-1-amine.

In a similar application, 4-bromo-2-nitrophenol (available from AldrichChemical Company) and 4-bromo-2-nitroaniline (available from Trans WorldChemicals, Inc.) can be reduced to 2-amino-4-bromophenol and4-bromo-1,2-diaminobenzene respectively using tin and hydrochloric acid.Alternatively, stannous chloride can be used as the reducing agent, asdescribed by Manjarrez et al., Rev. Soc. Quim. Mex. 30: 52 (1986).Reaction of 2-amino-4-bromophenol with trimethyl orthoformate inmethanol provides 5-bromobenzoxazole, as reported by Kunz et al., Org.Prep. Proced. Int. 22: 613 (1990). Similarly, condensationof4-bromo-1,2-diaminobenzene with formic acid in the presence of 6 Mhydrochloric acid gives 5(6)-bromobenzimidazole, as described byGoldsmith et al. in U.S. Pat. No. 3,325,271. 5(6)-Bromobenzimidazole canalso be made by brominating the commercially available benzimidazole(Aldrich Chemical Company) with bromine in aqueous ammonia according toPopov et al. in Soviet Union Patent No. 1,616,912. Applying thepreviously described Heck chemistry to 5-bromobenzoxazole and5(6)-bromobenzimidazole will produce(E)-N-methyl-4-(5-benzoxazolyl)-3-buten-1-amine and(E)-N-methyl-4-(5(6)-benzimidazolyl)-3-buten-1-amine, respectively. Inanother application of this chemistry, 4-bromo-1,2-diaminobenzene can becondensed with glyoxal hydrate to give 6-bromoquinoxaline, which cansubsequently be converted into(E)-N-methyl-4-(6-quinoxalinyl)-3-buten-1-amine. In yet anotherapplication, 2-amino-4-bromophenol can be converted into6-bromobenzoxazine by the action of 1,2-dihaloethane as described byBenoit et al., J. Pharm. Chim. 22: 544 (1935). Thus produced, the6-bromobenzoxazine can be protected as its N-tert-butoxycarbonylderivative and submitted to Heck coupling and removal of the protectinggroup to give (E)-N-methyl-4-(6-benzoxazinyl)-3-buten-1-amine.Furthermore, acetylation of 4-bromo-1,2-diaminobenzene with aceticanhydride followed by treatment with thallium (III) trifluoroacetate intrifluoroacetic acid, as described by Lau et al., Tetrahedron Lett. 22:1175 (1981), gives 4-acetamido-6-bromo-2-methylbenzoxazole which can beconverted into(E)-N-methyl-4-(6-(4-acetamido-2-methylbenzoxazol)yl)-3-buten-1-amineusing the Heck coupling.

Certain 4-amino-6-halobenzofurans, which are starting materials for theHeck reaction, are readily accessible by elaboration of the previouslydescribed 3-halo-5-methoxyanilines, synthesized as described by Emokpaeet al., J. Chem. Soc., Perkin Trans. 2(1): 14 (1977) and Liedholm, ActaChem. Scand., Ser. B, 38: 877 (1984). Thus, 3-bromo-5-methoxyaniline canbe demethylated with hydrobromic acid to give 3-amino-5-bromophenol.Protection of the amino group as its phthaloyl derivative and alkylationof the phenolic oxygen with allyl bromide and potassium carbonate willprovide the allyl phenyl ether. This latter material (either as the freeamine or the protected amine) can be induced to undergo Claisenrearrangement and ring closure to the corresponding2,3-dihydro-2-methylbenzofuran by a variety of well establishedchemistries, such as that of Kim et al., Heterocycles 36: 497 (1993) andthose reviewed by Lutz, Chem. Rev. 84: 205 (1984). The4-amino-6-bromo-2,3-dihydro-2-methylbenzofuran, thus produced, can beconverted into the target(E)-N-methyl-4-(6-(4-amino-2,3-dihydro-2-methylbenzofuran)yl)-3-buten-1-amineby the palladium catalyzed coupling reactions and associated chemistrydescribed earlier. This approach to the synthesis ofbenzofuran-containing alkenyl amines is general in the sense that avariety of allylic halides can be used to alkylate the phenol, thusproducing, after Claisen rearrangement and ring closure, a variety ofalkyl substituted 2,3-dihydrobenzofurans and 3,4-dihydrobenzopyrans.

Aryl substituted aliphatic amine compounds that possess a cyclopropylmoiety in the side chain can be prepared by a variety of methods. In onesynthetic approach, aryl substituted cyclopropyl analogs can be preparedfrom the aforementioned aryl substituted olefinic amine compounds. Arylsubstituted olefinic amine compounds possessing either an (E) or (Z)geometry can be converted to the corresponding trans and ciscyclopropane derivatives, respectively by treatment of the olefiniccompounds with methylene iodide and a zinc-copper couple using the typesof procedures set forth in H. E. Simmons et al., J. Amer. Chem. Soc. 81:4256-4264 (1959). In particular, compounds such as(E)-4-(3-aminophenyl)-3-buten-1-amine,(E)-N-methyl-4-(3-aminophenyl)-3-buten-1-amine,(E)-N-methyl-5-(3-aminophenyl)-4-penten-2-amine, and(E)-N-methyl-5-(3-methoxyphenyl)-4-penten-2-amine can be converted totheir corresponding cyclopropyl derivatives using the Simmons-Smithprocedure.

Compounds of the present invention which possess an arylmethyl etherskeleton, such as an N-methyl-2-[(3-aminophenyl)methoxy]-ethan-1-aminetype compound, can be prepared by a number of methods. In one approach,a 3-aminobenzyl alcohol type compound (N-protected as the phthalimide)can be condensed with the p-toluenesulfonate ester of ethanolamine,possessing a protected amine functionality, namely2-p-toluenesulfonyloxy-[N-methyl-N-(tert-butoxycarbonyl)]-ethan-1-amine.Typically a strong base such as sodium hydride and an aprotic dipolarsolvent such as N,N-dimethylformamide are used for the condensation. Thetert-butoxycarbonyl protecting group of the resulting arylmethyl ethertype compound can be removed with trifluoroacetic acid, followed byremoval of the phthaloyl group with methylamine or hydrazine affordingN-methyl-2-[(3-aminophenyl)methoxy]-ethan-1-amine. Substituted benzylalcohol starting materials such as 3-aminobenzyl alcohol arecommercially available from Aldrich Chemical Company. The phthalimide of3-aminobenzyl alcohol can be prepared by heating 3-aminobenzyl alcoholwith phthlic anhydride under reflux with azeotropic removal of wateraccording to the method of J. F. Bunnett et al., J. Org. Chem. 27:3836-3843 (1962). Protected amino side chain compounds such as2-p-toluenesulfonyloxy-[N-methyl-N-(tert-butoxycarbonyl)]-ethan-1-aminecan be prepared using the methods set forth in J. Christoffers, LiebigsAnn./Recl. (7): 1353-1358 (1997). By using this synthetic approach,substituted benzyl alcohol starting materials such as4-methyl-3-nitrobenzyl alcohol, 4-chloro-3-nitrobenzyl alcohol,3-nitrobenzyl alcohol, and 3,4-dimethoxybenzyl alcohol (commerciallyavailable from Acros Organics) can be elaborated to giveN-methyl-2-[(4-methyl-3-nitrophenyl)methoxy]-ethan-1-amine,N-methyl-2-[(4-chloro-3-nitrophenyl)methoxy]-ethan-1-amine,N-methyl-2-[(3-nitrophenyl)methoxy]-ethan-1-amine, andN-methyl-2-[(3,4-dimethoxyphenyl)methoxy]-ethan-1-amine, respectively.

Compounds of the present invention with an arylmethyl etherfunctionality and which also possess a branched side chain, such as anN-methyl-1-[(3-aminophenyl)methoxy]-propan-2-amine type compound, can beprepared by a number of methods. In one approach, a 3-aminobenzylalcohol type compound (N-protected as the phthalimide) can be alkylatedwith 1-bromo-2-propanol type compound containing an O-protecting group,such as 2-(2-bromo-1-methylethoxy)tetrahydro-2H-pyran. Typically astrong base such as sodium hydride and a solvent such asN,N-dimethylformamide or tetrahydrofuran are used for the alkylation.The tetrahydropyranyl protecting group of the resulting arylmethyl ethertype compound can be removed with aqueous sulfuric acid in methanol,affording 1-[(3-aminophenyl)methoxy]-propan-2-ol. The latter alcohol canbe elaborated to the corresponding methylamino compound by conversion toits p-toluenesulfonate ester by treatment with p-toluenesulfonylchloride, followed by tosylate displacement with methylamine and finallyremoval of the N-phthaloyl group affordingN-methyl-1-[(3-aminophenyl)methoxy]-propan-2-amine. Side chain compoundssuch as 2-(2-bromo-1-methylethoxy)tetrahydro-2H-pyran can be preparedfrom 1-bromo-2-propanol (commercially available from Aldrich ChemicalCompany) by treatment with 2,3-dihydropyran in dichloromethane withp-toluenesulfonic acid as a catalyst according to the methods of S. A.M. Nieuwenhuis et al., Tetrahedron 50: 13207-13230 (1994).

The manner in which optically active forms of arylmethoxy aliphaticamines, such as (2S)-N-methyl-1-[(3-aminophenyl)methoxy]-propan-2-aminetype compounds, are provided can vary. In one approach, a 3-aminobenzylalcohol type compound (N-protected as the phthalimide) can be alkylatedwith a chiral 1-bromo-2-propanol type compound containing anO-protecting group, such as(1S)-2-(2-bromo-1-methylethoxy)tetrahydro-2H-pyran using a base such assodium hydride and a solvent such as N,N-dimethylformamide ortetrahydrofuran. The tetrahydropyranyl protecting group of the resultingchiral arylmethyl ether type compound can be removed with aqueoussulfuric acid in methanol, affording(2S)-1-[(3-aminophenyl)methoxy]-propan-2-ol. The resulting chiralalcohol intermediate can be converted to its corresponding tosylate,followed by tosylate displacement with methylamine with inversion ofconfiguration, and finally removal of the N-phthaloyl group to give thechiral amine (2R)-N-methyl-1-[(3-aminophenyl)methoxy]-propan-2-amine.Chiral side chain compounds such as(1S)-2-(2-bromo-1-methylethoxy)tetrahydro-2H-pyran can be prepared from(2S)-1-bromo-2-propanol by treatment with 3,4-dihydro-2H-pyran indichloromethane with p-toluenesulfonic acid as a catalyst according tothe method of S. A. M. Nieuwenhuis et al., Tetrahedron 50: 13207-13230(1994). The required (2S)-1-bromo-2-propanol can be obtained from(S)-propylene oxide (commercially available from Fluka) by treatmentwith hydrogen bromide in acetic acid at 0° C. The corresponding opticalantipode, (2R)-N-methyl-1-[(3-aminophenyl)methoxy]-propan-2-amine can beprepared in an analogous manner from (R)-propylene oxide (commerciallyavailable from Fluka) by using the synthetic procedure of S. A. M.Nieuwenhuis et al. to prepare the tetrahydropyranyl ether of(2R)-1-bromo-2-propanol and by using the synthetic sequence describedabove.

Alternatively, the same chiral side-chain can be derived fromN-methyl-L-alanine and N-methyl-D-alanine (available from Sigma) byreduction with lithium aluminum hydride to give the correspondingN-methylaminopropanols, and subsequent reaction with di-tert-butyldicarbonate (to protect the amino group) and p-toluenesulfonyl chloride(to esterify the alcohol). These transformations are similar to thosereported by Schessinger et al., Tetrahedron Lett. 28: 2083-2086 (1987).The (S) and (R)1-p-toluenesulfonyloxy-N-methyl-N-(tert-butoxycarbonyl)-2-propanamineswhich result can be used to alkylate phthaloyl protected 3-aminobenzylalcohols in the same manner as described above for2-p-toluenesulfonyloxy-N-methyl-N-(tert-butoxycarbonyl)-1-ethanamine.

Other 3-aminobenzyl alcohols are provided by well-known transformationsof commercially available materials. Thus 3-aminoacetophenone, fromAldrich Chemical Company, can be reduced to racemic3-amino-α-methylbenzyl alcohol by sodium borohydride in the presence ofacetic acid as described by Nieminen et al., Tetrahedron Lett. 28:4725-8 (1987). Alternatively, the phthaloyl protected3-aminoacetophenone can be reduced with either of the enantiomers ofB-chlorodiisopino-campheylborane (DIP-chloride, Aldrich ChemicalCompany) to produce the protected, enantiomerically pure3-amino-α-methylbenzyl alcohol according to the procedures reported byBrown et al., Acc. Chem. Res. 25: 16 (1992). Other α-mono-substituted3-aminobenzyl alcohols can be accessed by addition of the appropriatealkyl- or aryllithium or alkyl- or arylmagnesium halide reagent to thephthaloyl protected 3-aminobenzaldehyde, which can be made fromcommercially available 3-nitrobenzaldehyde (Aldrich Chemical Company).Thus, treatment of 3-nitrobenzaldehyde with ethylene glycol andp-toluenesulfonic acid produces the ethylene acetal. The nitro group canthen be reduced with sodium borohydride to the amino group, which can beprotected as its phthaloyl derivative. Hydrolysis of the ethylene acetalwith aqueous acetic acid gives phthaloyl protected 3-aminobenzaldehyde.Addition of n-butyllithium to phthaloyl protected 3-aminobenzaldehydeyields the phthaloyl derivative of 1-(3-aminophenyl)-1-pentanol.Similarly di-substitution (methyl and alkyl or aryl) on the α-carbon ofthe benzyl alcohol can be accomplished by treatment of the phthaloylprotected 3-aminoacetophenone with alkyl- or aryllithium or alkyl- orarylmagnesium halide reagents. Alternatively, a variety ofα-mono-substituted and α,α-di-substituted 3-aminobenzyl alcohols areavailable by the method of Guijarro et al., Tetrahedron 49: 469-82(1993). Thus, 3-chloroaniline (Aldrich Chemical Company) is convertedinto its pivaloyl derivative and then treated sequentially withn-butyllithium, lithium metal in the presence of catalytic amount ofnaphthalene, and an aldehyde or ketone to produce the pivaloylderivatives of α-mono-substituted and α,α-di-substituted 3-aminobenzylalcohols, respectively. Thus, when this process is carried out usingcyclohexanone as the carbonyl component, the1-(N-pivaloyl-3-aminophenyl)cyclohexanol is the product. In a similarprocess, reported by Gross et al., J. Org. Chem. 58: 2104-9 (1993),3-bromoaniline is converted to its 3,3-(1,4-butanediyl)triazenederivative by diazotization and reaction with pyrrolidine. The3-bromophenyltriazene can then be converted, by treatment withsec-butyllithium, into the 3-lithiophenyltriazene, which can then bereacted with carbonyl electrophiles to give triazene protectedα-mono-substituted and α,α-di-substituted 3-aminobenzyl alcohols.Reaction of the protected (phthaloyl, pivaloyl, or triazene derivatives)3-aminobenzyl alcohols (with or without α-substitution) with sodiumhydride and either2-p-toluenesulfonyloxy-1-(N-methyl-N-(tert-butoxycarbonyl))ethanamine or1-p-toluenesulfonyloxy-2-(N-methyl-N-(tert-butoxycarbonyl)propanamine(the synthesis of which is described above), will provide, after removalof the protecting groups, the correspondingN-methyl-2-(3-aminophenyl)methoxy-1-ethanamines andN-methyl-1-(3-aminophenyl)methoxy-2-propanamines with or withoutsubstitution α to the aniline ring. The amine protecting groups used inthese ether syntheses can be removed by the following means: phthaloyl(hydrazine hydrate in methanol); pivaloyl (lithium aluminum hydride);3,3-(1,4-butanediyl)triazene (nickel-aluminum alloy in methanolicpotassium hydroxide); tert-butoxycarbonyl (trifluoroacetic acid). Thus,the reaction of phthaloyl protected 3-amino-α-methylbenzyl alcohol withsodium hydride and1-p-toluenesulfonyloxy-2-(N-methyl-N-(tert-butoxycarbonyl))propanamine,and subsequent treatment with hydrazine hydrate (to remove the phthaloylgroup) and then trifluoroacetic acid (to remove the tert-butoxycarbonylgroup), will provide N-methyl-1-(1-(3-aminophenyl)ethoxy)-2-propanamine.Either enantiomer of either component may be used or the racemate of onecomponent can be condensed with a single enantiomer of the other to givediasteriomeric amines, which are potentially separable bychromatographic methods. In another application of this chemistry, thetriazene derivative of 1-(3-aminophenyl)cyclohexanol can be reacted withsodium hydride and2-p-toluenesulfonyloxy-1-(N-methyl-N-(tert-butoxycarbonyl)ethanamine,and subsequently treated with nickel-aluminum alloy in methanolicpotassium hydroxide (to convert the triazene to the amino group) andthen trifluoroacetic acid, producingN-methyl-2-(1-(3-aminophenyl)cyclohexyloxy)-1-ethanamine.

Aromatic ring-substituted 3-aminobenzyl alcohols can also be used toproduce compounds of the present invention. The means by which suchring-substituted 3-aminobenzyl alcohols are produced can vary. Onemethod consists of reacting a substituted N-protected 3-haloaniline withn-butyllithium or sec-butyllithium followed by a formaldehyde equivalent(like paraformaldehyde), as described by Guijarro et al., Tetrahedron49: 469-82 (1993) and Gross et al., J. Org. Chem. 58: 2104-9 (1993).Using this technology, the various ring-substituted bromoanilines andfused ring aryl bromides described earlier (as useful in the Heckcoupling) are potential starting materials for production of thecorresponding benzyl alcohols. Thus, 3-bromo-5-methoxyaniline(synthesized as described by Emokpae et al., J. Chem. Soc., PerkinTrans. 2(1): 14-17 (1977)) can be converted into its triazenederivative, lithiated, and reacted with paraformaldehyde (as describedby Gross et al., J. Org. Chem. 58: 2104-9 (1993)). The resultingtriazene protected 3-amino-5-methoxybenzyl alcohol can be reacted withsodium hydride and2-p-toluenesulfonyloxy-N-methyl-N-(tert-butoxycarbonyl)-1-ethanamine.Removal of the protecting groups (as previously described) then affordsN-methyl-2-(3-amino-5-methoxyphenyl)methoxy-1-ethanamine.

Certain other ring-substituted and fused-ring benzyl alcohols arereadily prepared from the corresponding aldehydes and carboxylic acidsby reduction with a hydride reducing agent. For example, M. Bianchi etal., Chim. Ind. 49: 392 (1967) described the conversion of3-amino-4-hydroxybenzoic acid (Aldrich Chemical Company) into itsformamide by refluxing formic acid and the subsequent heating of theformamide to produce 5-benzoxazolecarbdxylic acid. Treatment of the acidwith thionyl chloride produces the corresponding acid chloride which canthen be reduced to 5-(hydroxymethyl)benzoxazole. This fused-ring benzylalcohol can be condensed with1-p-toluenesulfonyloxy-N-methyl-N-(tert-butoxycarbonyl)-2-propanamineusing sodium hydride to give, after deprotection,N-methyl-1-(5-benzoxazolyl)methoxy-2-propanamine. In another similarcase, piperonylic acid (Aldrich Chemical Company) can be nitrated togive 5-nitropiperonylic acid (5-nitro-3,4-methylenedioxybenzoic acid),which can subsequently be reduced to 5-aminopiperonyl alcohol(5-amino-3,4-methylenedioxybenzyl alcohol) by sequential treatment withtin in hydrochloric acid and lithium aluminum hydride. Protection ofthis amine as its phthaloyl derivative, followed by reaction with sodiumhydride and2-p-toluenesulfonyloxy-N-methyl-N-(tert-butoxycarbonyl)-1-ethanamineresults in formation of the benzyl ether compound. Subsequent removal ofthe protecting groups, affordsN-methyl-2-(5-amino-3,4-methylenedioxyphenyl)methoxy-1-ethanamine.

Compounds of the present invention which possess an arylmethyl etherfunctionality with a cyclic amine fragment, such as a3-((2-pyrrolidinylethoxy)methyl)phenylamine type compound can beprepared by a variety of methods. By one synthetic approach, thep-toluenesulfonate ester of a 3-aminobenzyl alcohol type compound(N-protected as the phthalimide) can be used to alkylate1-(2-hydroxyethyl)pyrrolidine (commercially available from AldrichChemical Company) in the presence of a base such as sodium hydride in asolvent such as tetrahydrofuran or N,N-dimethylformamide. The phthaloylprotecting group of the resulting intermediate can be removed bytreatment with methylamine or hydrazine yielding the3-((2-pyrrolidinylethoxy)methyl)phenylamine.

Compounds of the present invention which possess an arylmethyl etherfunctionality with a chiral azacyclic fragment, such as3-((pyrrolidin-2(S)-ylmethoxy)methyl)phenylamine and3-(((1-methylpyrrolidin-2(S)-yl)methoxy)methyl)phenylamine typecompounds can be prepared by a number of methods. By one syntheticapproach, the p-toluenesulfonate ester of a 3-aminobenzyl alcohol typecompound (N-protected as the phthalimide) can be used to alkylate(S)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol in the presence of abase such as sodium hydride in a solvent such as tetrahydrofuran orN,N-dimethylformamide. The tert-butoxycarbonyl group can be removed withstrong acid such as trifluoroacetic acid or hydrochloric acid and thephthaloyl group can be removed by treatment with hydrazine ormethylamine producing 3-((pyrrolidin-2(S)-ylmethoxy)methyl)phenylamine.The required (S)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol iscommercially available from Aldrich Chemical Company. The correspondingenantiomer, 3-((pyrrolidin-2(R)-ylmethoxy)methyl)phenylamine can beprepared in an analogous manner from(R)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol (commerciallyavailable from Aldrich Chemical Company). It should be mentioned that(S)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol and(R)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol can be preparedaccording to the methods of D. A. Evans et al., J. Am. Chem. Soc. 101:371-378 (1979) and B. D. Harris et al., Heterocycles 24: 1045-1060(1986) starting from commercially available (Aldrich Chemical Company)D-proline and L-proline. Compounds of the present invention such as3-(((1-methylpyrrolidin-2(S)-yl)methoxy)methyl)phenylamine can beprepared in a similar manner by the alkylation of(S)-1-methyl-2-pyrrolidinemethanol (available from Aldrich ChemicalCompany) with the previously mentioned p-toluenesulfonate ester of a3-aminobenzyl alcohol (N-protected as the phthalimide), followed byremoval of the tert-butoxycarbonyl and phthaloyl protecting groups. Thecorresponding enatiomer of the above N-methyl compound, namely3-(((1-methylpyrrolidin-2(R)-yl)methoxy)methyl)phenylamine can beprepared in a similar manner by the alkylation of(R)-1-methyl-2-pyrrolidinemethanol with the previously mentionedp-toluenesulfonate ester of a 3-aminobenzyl alcohol (N-protected as thephthalimide), followed by removal of the tert-butoxycarbonyl andphthaloyl protecting groups. The required(R)-1-methyl-2-pyrrolidinemethanol can be prepared by the method of R.E. Gawley et al., J. Org. Chem. 60 (18): 5763-5769 (1995).

Compounds of the present invention which possess an arylmethyl etherfunctionality with a chiral azacyclic fragment, such as3-((2(S)-azetidinylmethoxy)methyl)phenylamine and3-(((1-methyl-2(S)-azetidinyl)-methoxy)methyl)phenylamine type compoundscan be prepared by a variety of synthetic methods. In one syntheticapproach, the p-toluenesulfonate ester of a 3-aminobenzyl alcohol typecompound (N-protected as the phthalimide) can be used to alkylate(S)-1-(tert-butoxycarbonyl)-2- azetidinemethanol in the presence of abase such as sodium hydride in a solvent such as tetrahydrofuran orN,N-dimethylformamide. The tert-butoxycarbonyl group can be removed witha strong acid such as trifluoroacetic acid or hydrochloric acid and thephthaloyl group can be removed by treatment with hydrazine ormethylamine affording 3-((2(S)-azetidinylmethoxy)methyl)phenylamine. Therequisite nonracemic compound,(S)-1-tert-butoxycarbonyl)-2-azetidinemethanol can be prepared from(S)-2-azetidinecarboxylic acid (commercially available from AldrichChemical Company) using the method of M. A. Abreo et al., J. Med. Chem.39: 817-825 (1996). The enantiomeric azetidinyl compound,3-((2(R)-azetidinylmethoxy)-methyl)phenylamine can be prepared in ananalogous way by coupling 3-aminobenzyl alcohol type compound(N-protected as the phthalimide) with(R)-1-(benzyloxycarbonyl)-2-azetidinemethanol, followed by treatmentwith base, such as methanolic potassium hydroxide to remove thebenzyloxycarbonyl protecting group and treatment with hydrazine ormethylamine to remove the phthaloyl protecting group. The required(R)-1-(benzyloxycarbonyl)-2-azetidinemethanol can be prepared fromD-methionine using the methodology of M. A. Abreo et al., J. Med. Chem.39: 817-825 (1996). Compounds of the present invention such as3-(((1-methyl-2(S)-azetidinyl)methoxy)methyl)phenylamine and itsenantiomeric compound, 3-(((1-methyl-2(R)-azetidinyl)methoxy)methyl)phenylamine can be prepared by methylation of the previously describedsecondary amino compounds, 3-((2(S)-azetidinylmethoxy)methyl)phenylamineand 3-((2(R)-azetidinylmethoxy)methyl)phenylamine, respectively, eachN-protected as the phthalimide. Methylation methods employing aqueousformaldehyde and sodium cyanoborohydride as described by M. A. Abreo etal., J. Med. Chem. 39: 817-825 (1996) can be used. Removal of thephthaloyl group can be accomplished under mild conditions usning sodiumborohydride in 2-propanol as described by J. O. Osby et al., TetrahedonLett. 25(20): 2093-2096 (1984).

Using this approach, other compounds containing arylmethyl ether andazacyclic functionality can be made. Thus, the commercially available3-pyrrolidinol and 3-quinuclidinol (both from Aldrich Chemical Company)can be converted into their N-tert-butoxycarbonyl derivatives byreaction with di-tert-butyl dicarbonate. Subsequent alkylation withsodium hydride and the p-toluenesulfonate ester of phthaloyl protected3-aminobenzyl alcohol in N,N-dimethylformamide, followed by removal ofthe protecting groups, will generate 3-(3-aminobenzyloxy)pyrrolidine and3-(3-aminobenzyloxy)quinuclidine, respectively. Alternatively, thealkylation can be carried out with 3-nitrobenzyl bromide (AldrichChemical Company) to produce the corresponding3-(3-nitrobenzyloxy)pyrrolidine and 3-(3-nitrobenzyloxy)quinuclidine.

Compounds of the present invention may contain a thiazoline ring. Themethods by which such thiazoline containing compounds can be synthesizedcan vary. One method involves the condensation of a thioamide orthiourea with an α-haloaldehyde, such as 2-chloroacetaldehyde or2-bromoacetaldehyde. The requisite thioamides and thioureas can beproduced in a number of ways. For instance, the alkoxide of3-nitrobenzyl alcohol (Aldrich Chemical Company) can be converted to3-chloro-1-((3-nitrophenyl)methoxy)propane by treatment with3-chloro-1-iodopropane (Aldrich Chemical Company). Conversion of thiscompound to the corresponding amine can be accomplished by a variety ofmethods known in the art, such as by Gabriel synthesis (Gibson andBradshaw, Agnew. Chem. Int. Eng. Ed. 7: 919 (1968)), whereby the alkylchloride is converted to the phthalimide followed by removal of thephthaloyl protecting group with hydrazine. Then, the resulting3-((3-nitrophenyl)methoxy)-1-propanamine can be converted into itsthiourea by treatment with thiocyanic acid in DMF. This mono-substitutedthiourea can then be cyclized to formN-(2-thiazolyl)-3-((3-nitrophenyl)methoxy)-1-propanamine usingchloracetaldehyde (Aldrich Chemical Company) in the presence ofmagnesium sulfate as described by Bramley et al., J. Chem. Soc. PerkinTrans. I 3: 639 (1987). Finally, any number of methods known to the artof organic synthesis can be used to reduce the aryl nitro group to givethe desired aryl amine,N-(2-thiazolyl)-3-((3-aminophenyl)methoxy)-1-propanamine. One suchmethod is the use of hexarubidiumcarbonyl andN,N,N,N-tetramethyl-1,3-propanediamine according to the method ofKiyotomi et al., J. Mol. Catal. 88: L267 (1994). Alternatively, thethiourea of 3-((3-nitrophenyl)methoxy)-1-propanamine can be cyclized toform 3-(3-((3-nitrophenyl)methoxy)propyl)-2,3-dihydrothiazolin-2-imine,using chloroacetaldehyde in the presence of hydrochloric acid asdescribed by Bramley et al., J. Chem. Soc. Perkin Trans. I 3: 639(1987). Reduction to the corresponding aryl amine can be accomplished asdescribed above.

The present invention relates to a method for providing prevention of acondition or disorder to a subject susceptible to such a condition ordisorder, and for providing treatment to a subject suffering therefrom.For example, the method comprises administering to a patient an amountof a compound effective for providing some degree of prevention of theprogression of a CNS disorder (i.e., provide protective effects),amelioration of the symptoms of a CNS disorder, and amelioration of therecurrence of a CNS disorder. The method involves administering aneffective amount of a compound selected from the general formulae whichare set forth hereinbefore. The present invention relates to apharmaceutical composition incorporating a compound selected from thegeneral formulae which are set forth hereinbefore. Optically activecompounds can be employed as racemic mixtures or as enantiomers. Thecompounds can be employed in a free base form or in a salt form (e.g.,as pharmaceutically acceptable salts). Examples of suitablepharmaceutically acceptable salts include inorganic acid addition saltssuch as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate;organic acid addition salts such as acetate, galactarate, propionate,succinate, lactate, glycolate, malate, tartrate, citrate, maleate,fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; saltswith acidic amino acid such as aspartate and glutamate; alkali metalsalts such as sodium salt and potassium salt; alkaline earth metal saltssuch as magnesium salt and calcium salt; ammonium salt; organic basicsalts such as trimethylamine salt, triethylamine salt, pyridine salt,picoline salt, dicyclohexylamine salt, and N,N′-dibenzylethylenediaminesalt; and salts with basic amino acid such as lysine salt and argininesalt. The salts may be in some cases hydrates or ethanol solvates.Representative salts are provided as described in U.S. Pat. Nos.5,597,919 to Dull et al., 5,616,716 to Dull et al. and 5,663,356 toRuecroft et al.

Compounds of the present invention exhibit activity at acetylcholinereceptors, are useful towards modulating release of ligands involved inneurotransmission. Compounds of the present invention are selective tocertain nicotinic acetylcholine receptor subtypes, and can act asagonists at those receptor subtypes. Compounds of the present inventionare useful for treating those types of conditions and disorders forwhich other types of nicotinic compounds have been proposed astherapeutics. See, for example, those types of conditions and disordersset forth in Williams et al. DN&P 7(4):205-227 (1994), Arneric et al.,CNS Drug Rev. 1(1):1-26 (1995), Arneric et al., Exp. Opin. Invest. Drugs5(1): 79-100 (1996), Bencherif et al., JPET 279:1413-1421 (1996),Lippiello et al., JPET 279:1422-1429 (1996), Damaj et al., Neuroscience(1997), Holladay et al., J. Med. Chem 40(28): 4169-4194 (1997), Bannonet al., Science 279: 77-80 (1998), PCT WO 94/08992, PCT WO 96/31475, PCTWO 97/19059, European Patent Application 857,725, and U.S. Pat. Nos.5,278,176 to Lin, 5,583,140 to Bencherif et al., 5,597,919 to Dull etal., 5,604,231 to Smith et al., 5,616,716 to Dull et al. and 5,811,442to Bencherif et al. the disclosures of which are incorporated herein byreference in their entireties. Compounds of the present invention can beused to treat presenile dementia (early onset Alzheimer's disease),senile dementia (dementia of the Alzheimer's type), Parkinsonismincluding Parkinson's disease, anxiolysis, attention deficithyperactivity disorder, depression, dyslexia, epilepsy, Huntington'schorea, hyperkinesia, mania, neuro-endocrine disorders, schizophrenia,sleep disorders, tardive dyskinesia, Tourette's syndrome, autism, anddysregulation of food intake (e.g., bulimia and anorexia). Compounds ofthe present invention can be used as anti-infectious agents (e.g., totreat bacterial and viral infections), anti-inflammatory agents (e.g.,to treat acute cholangitis, aphteous stomatitis, and ulcerativecolitis), anti-neoplastic agents, inhibitors of cytokines release (e.g.,to treat symptoms associated with cachexia, inflammation,neurodegenerative diseases, viral infection and neoplasia), modifiers ofthe vasculature tone (e.g., as occurs in stroke patients), and as agentsto treat conditions associated with microcirculation (e.g., to treatsymptoms associated with Raynaud's disease and Raynaud syndrome).Compounds of the present invention can be used as analgesics, intreating substance abuse withdrawal and in substitution therapies, intreating inflammatory bowel disease, in treating cardiovasculardisfunction, as depolarizing muscle relaxants, and as probes forneuro-imaging and in the life sciences.

The pharmaceutical composition also can include various other componentsas additives or adjuncts. Exemplary pharmaceutically acceptablecomponents or adjuncts which are employed in relevant circumstancesinclude antioxidants, free radical scavenging agents, peptides, growthfactors, antibiotics, bacteriostatic agents, immunosuppressives,anticoagulants, buffering agents, anti-inflammatory agents,anti-pyretics, time release binders, anaesthetics, steroids andcorticosteroids. Such components can provide additional therapeuticbenefit, act to affect the therapeutic action of the pharmaceuticalcomposition, or act towards preventing any potential side effects whichmay be posed as a result of administration of the pharmaceuticalcomposition. In certain circumstances, a compound of the presentinvention can be employed as part of a pharmaceutical composition withother compounds intended to prevent or treat a particular disorder.

The manner in which the compounds are administered can vary. Thecompounds can be administered by inhalation (e.g., in the form of anaerosol either nasally or using delivery articles of the type set forthin U.S. Pat. No. 4,922,901 to Brooks et al.); topically (e.g., in lotionform); orally (e.g., in liquid form within a solvent such as an aqueousor non-aqueous liquid, or within a solid carrier); intravenously (e.g.,within a dextrose or saline solution); as an infusion or injection(e.g., as a suspension or as an emulsion in a pharmaceuticallyacceptable liquid or mixture of liquids); intrathecally; intracerebroventricularly; or transdermally (e.g., using a transdermal patch).Although it is possible to administer the compounds in the form of abulk active chemical, it is preferred to present each compound in theform of a pharmaceutical composition or formulation for efficient andeffective administration. Exemplary methods for administering suchcompounds will be apparent to the skilled artisan. For example, thecompounds can be administered in the form of a tablet, a hard gelatincapsule or as a time release capsule. As another example, the compoundscan be delivered transdermally using the types of patch technologiesavailable from Novartis and Alza Corporation. The administration of thepharmaceutical compositions of the present invention can beintermittent, or at a gradual, continuous, constant or controlled rateto a warm-blooded animal, (e.g., a mammal such as a mouse, rat, cat,rabbit, dog, pig, cow, or monkey); but advantageously is preferablyadministered to a human being. In addition, the time of day and thenumber of times per day that the pharmaceutical formulation isadministered can vary. Administration preferably is such that the activeingredients of the pharmaceutical formulation interact with receptorsites within the body of the subject that affect the functioning of theCNS. More specifically, in treating a CNS disorder administrationpreferably is such so as to optimize the effect upon those relevantreceptor subtypes which have an effect upon the functioning of the CNS,while minimizing the effects upon muscle-type receptor subtypes. Othersuitable methods for administering the compounds of the presentinvention are described in U.S. Pat. No. 5,604,231 to Smith et al. and5,811,442 to Bencherif et al.

The appropriate dose of the compound is that amount effective to preventoccurrence of the symptoms of the disorder or to treat some symptoms ofthe disorder from which the patient suffers. By “effective amount”,“therapeutic amount” or “effective dose” is meant that amount sufficientto elicit the desired pharmacological or therapeutic effects, thusresulting in effective prevention or treatment of the disorder. Thus,when treating a CNS disorder, an effective amount of compound is anamount sufficient to pass across the blood-brain barrier of the subject,to bind to relevant receptor sites in the brain of the subject, and toactivate relevant nicotinic receptor subtypes (e.g., provideneurotransmitter secretion, thus resulting in effective prevention ortreatment of the disorder). Prevention of the disorder is manifested bydelaying the onset of the symptoms of the disorder. Treatment of thedisorder is manifested by a decrease in the symptoms associated with thedisorder or an amelioration of the recurrence of the symptoms of thedisorder.

The effective dose can vary, depending upon factors such as thecondition of the patient, the severity of the symptoms of the disorder,and the manner in which the pharmaceutical composition is administered.For human patients, the effective dose of typical compounds generallyrequires administering the compound in an amount sufficient to activaterelevant receptors to effect neurotransmitter (e.g., dopamine) releasebut the amount should be insufficient to induce effects on skeletalmuscles and ganglia to any significant degree. The effective dose ofcompounds will of course differ from patient to patient but in generalincludes amounts starting where CNS effects or other desired therapeuticeffects occur, but below the amount where muscular effects are observed.

Typically, the effective dose of compounds generally requiresadministering the compound in an amount of less than 5 mg/kg of patientweight. Often, the compounds of the present invention are administeredin an amount from 1 mg to less than 100 ug/kg of patient weight,frequently between about 1 ug to less than 100 ug/kg of patient weight,and preferably between about 1 ug to about 50 ug/kg of patient weight.For compounds of the present invention that do not induce effects onmuscle type nicotinic receptors at low concentrations, the effectivedose is less than 5 mg/kg of patient weight; and often such compoundsare administered in an amount from 1 ug to less than 5 mg/kg of patientweight. The foregoing effective doses typically represent that amountadministered as a single dose, or as one or more doses administered overa 24 hour period.

For human patients, the effective dose of typical compounds generallyrequires administering the compound in an amount of at least about 0.1,often at least about 10, and frequently at least about 25 ug/24hr./patient. For human patients, the effective dose of typical compoundsrequires administering the compound which generally does not exceedabout 500, often does not exceed about 400, and frequently does notexceed about 300 ug/24 hr./patient. In addition, administration of theeffective dose is such that the concentration of the compound within theplasma of the patient normally does not exceed 500 ng/ml, and frequentlydoes not exceed 100 ng/ml.

The compounds useful according to the method of the present inventionhave the ability to pass across the blood-brain barrier of the patient.As such, such compounds have the ability to enter the central nervoussystem of the patient. The log P values of typical compounds, which areuseful in carrying out the present invention are generally greater thanabout 0, often are greater than about 0.5, and frequently are greaterthan about 1. The log P values of such typical compounds generally areless than about 3.5, often are less than about 3, and sometimes are lessthan about 2.5. Log P values provide a measure of the ability of acompound to pass across a diffusion barrier, such as a biologicalmembrane. See, Hansch, et al., J. Med. Chem. 11:1 (1968).

The compounds useful according to the method of the present inventionhave the ability to bind to, and in most circumstances, cause activationof, nicotinic cholinergic receptors of the brain of the patient (e.g.,such as those receptors that modulate dopamine release). As such, suchcompounds have the ability to express nicotinic pharmacology, and inparticular, to act as nicotinic agonists. The receptor binding constantsof typical compounds useful in carrying out the present inventiongenerally exceed about 0.1 nM, often exceed about 1 nM, and frequentlyexceed about 10 nM. The receptor binding constants of such typicalcompounds generally are less than about 1 uM, often are less than about100 nM, and frequently are less than about 50 nM. Receptor bindingconstants provide a measure of the ability of the compound to bind tohalf of the relevant receptor sites of certain brain cells of thepatient. See, Cheng, et al., Biochem. Pharmacol. 22:3099 (1973).

The compounds useful according to the method of the present inventionhave the ability to demonstrate a nicotinic function by effectivelyneurotransmitter secretion from, nerve ending preparations (e.g.,striatal synaptosomes). As such, such compounds have the ability tocause relevant neurons to become activated, and to release or secretedopamine or other neurotransmitters. Generally, typical compounds usefulin carrying out the present invention are potent in eliciting relevantreceptor activation. Generally, typical compounds useful in carrying outthe present invention effectively provide for the secretion of dopaminein amounts of at least about 50 percent, often at least about 75percent, and frequently at least about 100 percent, of that maximallyprovided by (S)-(−)-nicotine.

The compounds of the present invention, when employed in effectiveamounts in accordance with the method of the present invention, lack theability to elicit activation of nicotinic receptors of human muscle toany significant degree. In that regard, the compounds of the presentinvention demonstrate poor ability to cause isotopic rubidium ion fluxthrough nicotinic receptors in cell preparations expressing muscle-typenicotinic acetylcholine receptors. Thus, such compounds exhibit receptoractivation constants or EC50 values (i.e., which provide a measure ofthe concentration of compound needed to activate half of the relevantreceptor sites of the skeletal muscle of a patient) which are extremelyhigh (i.e., greater than about 100 uM). Generally, typical preferredcompounds useful in carrying the present invention activate isotopicrubidium ion flux by less than 15 percent, often by less than 5 percent,of that maximally provided by S(−)nicotine.

The compounds of the present invention, when employed in effectiveamounts in accordance with the method of the present invention, areselective to certain relevant nicotinic receptors, but do not causesignificant activation of receptors associated with undesirable sideeffects. By this is meant that a particular dose of compound resultingin prevention and/or treatment of a CNS disorder, is essentiallyineffective in eliciting activation of certain ganglionic-type nicotinicreceptors. This selectivity of the compounds of the present inventionagainst those receptors responsible for cardiovascular side effects isdemonstrated by a lack of the ability of those compounds to activatenicotinic function of adrenal chromaffin tissue. As such, such compoundshave poor ability to cause isotopic rubidium ion flux through nicotinicreceptors in cell preparations derived from the adrenal gland.Generally, typical preferred compounds useful in carrying out thepresent invention activate isotopic rubidium ion flux by less than 15percent, often by less than 5 percent, of that maximally provided byS(−)nicotine.

Compounds of the present invention, when employed in effective amountsin accordance with the method of the present invention, are effectivetowards providing some degree of prevention of the progression of CNSdisorders, amelioration of the symptoms of CNS disorders, andamelioration to some degree of the recurrence of CNS disorders. However,such effective amounts of those compounds are not sufficient to elicitany appreciable side effects, as is demonstrated by decreased effects onpreparations believed to reflect effects on the cardiovascular system,or effects to skeletal muscle. As such, administration of compounds ofthe present invention provides a therapeutic window in which treatmentof certain CNS disorders is provided, and side effects are avoided. Thatis, an effective dose of a compound of the present invention issufficient to provide the desired effects upon the CNS, but isinsufficient (i.e., is not at a high enough level) to provideundesirable side effects. Preferably, effective administration of acompound of the present invention resulting in treatment of CNSdisorders occurs upon administration of less ⅓, frequently less than ⅕,and often less than {fraction (1/10)}, that amount sufficient to causeany side effects to a significant degree.

The following examples are provided to illustrate the present invention,and should not be construed as limiting thereof.

EXAMPLE 1

Determination of Binding to Relevant Receptor Sites

Binding of the compounds to relevant receptor sites was determined inaccordance with the techniques described in U.S. Pat. No. 5,597,919 toDull et al. Inhibition constants (Ki values), reported in nM, werecalculated from the IC₅₀ values using the method of Cheng et al.,Biochem, Pharmacol. 22:3099 (1973).

EXAMPLE 2

Determination of Dopamine Release

Dopamine release was measured using the techniques described in U.S.Pat. No. 5,597,919 to Dull et al. Release is expressed as a percentageof release obtained with a concentration of (S)-(−)-nicotine resultingin maximal effects. Reported EC₅₀ values are expressed in nM, andE_(max) values represent the amount released relative to(S)-(−)-nicotine on a percentage basis.

EXAMPLE 3

Determination of Interaction with Muscle Receptors

The determination of the interaction of the compounds with musclereceptors was carried out in accordance with the techniques described inU.S. Pat. No. 5,597,919 to Dull et al. The maximal activation forindividual compounds (E_(max)) was determined as a percentage of themaximal activation induced by (S)-(−)-nicotine. Reported E_(max) valuesrepresent the amount released relative to (S)-(−)-nicotine on apercentage basis.

EXAMPLE 4

Determination of Interaction with Ganglion Receptors

The determination of the interaction of the compounds with ganglionicreceptors was carried out in accordance with the techniques described inU.S. Pat. No. 5,597,919 to Dull et al. The maximal activation forindividual compounds (E_(max)) was determined as a percentage of themaximal activation induced by (S)-(−)-nicotine. Reported E_(max) valuesrepresent the amount released relative to (S)-(−)-nicotine on apercentage basis.

EXAMPLE 5

Determination of Log P Value

Log P values, which have been used to assess the relative abilities ofcompounds to pass across the blood-brain barrier (Hansch, et al., J.Med. Chem. ii:1 (1968)), were calculated using the Cerius² softwarepackage Version 3.5 by Molecular Simulations, Inc.

EXAMPLE 6

Sample No. 1 is (E)-4-(3-aminophenyl)-3-buten-1-amine, which wasprepared in accordance with the following techniques:

N-3-(Butenyl)phthalimide

N-3-(butenyl)phthalimide was prepared as a white, crystalline powder, mp52-52.5° C. in 92.9% using the procedure of Frank et al., J Org. Chem.43:2947 (1978).

(E)-N-[4-(3-Aminophenyl)-3-butenyl]phthalimide

Under a nitrogen atmosphere, a mixture of N-3-(butenyl)phthalimide (4.22g, 21.0 mmol), 3-bromoaniline (3.50 g, 20.4 mmol, Aldrich ChemicalCompany), palladium(II) acetate (46.0 mg, 0.20 mmol),tri-o-tolylphosphine (248 mg, 0.81 mmol), triethylamine (5.81 g, 57.4mmol), and acetonitrile (8 mL) was stirred and heated at 130° C. for 21h. Upon cooling to ambient temperature, the solids were partitionedbetween water (100 mL) and CH₂Cl₂ (100 mL). The aqueous phase wasseparated and extracted with CH₂Cl₂ (75 mL). The combined CH₂Cl₂extracts were washed with water (70 mL), filtered through Celite® filteraid (8 g), washing the filter cake with CH₂Cl₂ (25 mL). The filtrate wasdried (Na₂SO₄), filtered, and concentrated on a rotary evaporator. Theresulting residue was vacuum dried at 45° C. for 18 h to give 6.36 g ofa light-yellow, lumpy powder. The product was recrystallized fromCH₂Cl₂-2-propanol, filtered, washed with cold 2-propanol (2×10 mL) andvacuum dried at 50° C. for 2 h to give 5.00 g (84.0%) of a light-yellowpowder. TLC analysis on silica gel, eluting with CHCl₃-methanol (98:2,v/v) indicated the presence of impurities. Consequently, the product wasrecrystallized from DMF-water, filtered, washed with cold 2-propanol(3×2 mL), and vacuum dried at 50° C. for 18 h to give 4.64 g (78.0%) ofa yellow powder, mp 159-162° C. An analytical sample was recrystallizedfrom ethyl acetate-hexane (1:2, v/v) affording a light-beige powder, mp159-162° C., R_(f) 0.41 in ethyl acetate-hexane (1:1, v/v).

(E)-4-(3-Aminophenyl)-3-buten-1-amine

A mixture of (E)-N-[4-(3-aminophenyl)-3-butenyl]phthalimide (3.50 g,12.0 mmol) in ethanol (50 mL) was treated with 50 g of a 25% (w/w)solution of methylamine in ethanol. The resulting yellow solution wasstirred at room temperature for 3 h and concentrated on a rotaryevaporator. The product was vacuum dried at 50° C. for 1 h to give 4.26g of a viscous, orange-yellow oil. The oil was purified by columnchromatography on silica gel (200 g), eluting with methanol-concentratedammonium hydroxide (10:1, v/v). Based upon TLC analysis, selectedfractions were combined and concentrated on a rotary evaporator. Theproduct was purified by vacuum distillation (bulb to bulb) to give 124mg (6.4%) of a colorless oil, bp 105-110° C. at 0.075 mm Hg.Purification of a second fraction by vacuum distillation produced anadditional 141 mg of a colorless oil, bp 104-105° C. at 0.075 mm Hg,bringing the total yield to 249 mg (12.8%).

Sample No. 1 exhibits a log P of 1.04, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The compound exhibits a Ki of 542 nM. The bindingconstant indicates that the compound exhibits high affinity binding tocertain CNS nicotinic receptors.

Sample No. 1 exhibits an EC₅₀ value of 12600 nM and an E_(max) value of74% for dopamine release, indicating that the compound inducesneurotransmitter release thereby exhibiting known nicotinicpharmacology.

Sample No. 1 exhibits an E_(max) of 0% (at a concentration of 100 uM) atmuscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of4% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but does not show undesirable muscle and ganglioneffects to any significant degree.

EXAMPLE 7

Sample No. 2 is (E)-N-methyl-4-(3-aminophenyl)-3-buten-1-amine, whichwas prepared in accordance with the following techniques:

N-Methyl-3-buten-1-amine

Under a nitrogen atmosphere, anhydrous DMF (40 mL) was added via syringeto methylamine (40 mL, 43.2 g, 1.4 mol, condensed from the gas phase) at−78° C. Anhydrous potassium carbonate (19.36 g, 140 mmol) was added tothe stirring solution, followed by 4-bromo-1-butene (18.9 g, 140 mmol,Aldrich Chemical Company). The resulting mixture was allowed to slowlywarm to ambient temperature over 16 h. The mixture was poured into water(150 mL) and extracted with ether (8×50 mL). The combined ether extractswere dried (Na₂SO₄), filtered, and distilled at atmospheric pressure togive 6.86 g (57.6%) of a colorless oil, bp 80-82° C.

N-Methyl-N-(3-buten-1-yl)benzamide

Under a nitrogen atmosphere, a solution of N-methyl-3-buten-1-amine(6.86 g, 80.6 mmol) in dichloromethane (100 mL) was cooled to 0° C., andtriethylamine (17.93 g, 177.2 mmol) and 4-(N,N-dimethylamino)pyridine(207 mg) were added. A solution of benzoyl chloride (11.89 g, 84.6 mmol)in dichloromethane (60 mL) was added dropwise via addition funnel over 1h at 0-5° C. The resulting turbid mixture was stirred 3 h at 0° C. Themixture was then washed in succession with 1 M HCl solution (3×75 mL),5% NaHCO₃ solution (3×100 mL), and water (100 mL). The organic phase wasdried (Na₂SO₄), filtered, and concentrated on a rotary evaporator to ayellow oil (12.66 g). Vacuum distillation using a 6 in. Vigreaux columnand a short path distillation apparatus afforded 8.58 g (56.3%) of acolorless oil, bp 100-103° C. at 0.1 mm Hg.

(E)-N-Methyl-N-[4-(3-aminophenyl)-3-buten-1-yl]benzamide

Under a nitrogen atmosphere, a mixture ofN-methyl-N-(3-buten-1-yl)benzamide (2.15 g, 11.36 mmol), 3-iodoaniline(2.49 g, 11.36 mmol, Aldrich Chemical Company), palladium(II) acetate(25.5 mg, 0.11 mmol), and triethylamine (2.30 g, 22.70 mmol) was stirredand heated under reflux at 105-110° C. (oil bath temperature) for 52 h.The dark-brown solution was allowed to cool to ambient temperature andwas diluted with water (20 mL) and CHCl₃ (40 mL). The water layer wasseparated and extracted with CHCl₃ (2×10 mL). The combined CHCl₃extracts were washed with saturated NaCl solution (10 mL), dried(CHCl₃), filtered, and concentrated by rotary evaporation. Furtherdrying under high vacuum (0.3 mm Hg) for 15 h produced a viscous, brownoil (3.59 g). The crude material was purified by column chromatographyon silica gel (155.5 g, 4.0 cm i.d.×60.5 cm column) eluting with EtOAc(25→67%, v/v) in CHCl₃. Fractions containing the product (R_(f) 0.34 inEtOAc-CHCl₃, 1:1, v/v) were combined, concentrated by rotaryevaporation, and vacuum dried at 45° C. for 15 h to give 1.60 g (50.2%)of an amber oil.

(E)-N-Methyl-4-(3-aminophenyl)-3-buten-1-amine

A solution of (E)-N-methyl-N-[4-(3-aminophenyl)-3-buten-1-yl]benzamide(1.52 g, 5.42 mmol) in 6 M HCl solution (55 mL) was stirred and heatedunder reflux at 105° C. (oil bath temperature) for 17.5 h. The resultingdark-brown solution was allowed to cool to ambient temperature and wasfurther cooled to 0° C. A 20% NaOH solution (85 mL) was carefully addedwith stirring giving pH 13. The resulting mixture was extracted withCHCl₃ (3×50 mL). The combined tan CHCl₃ extracts were washed withsaturated NaCl solution (50 mL), dried (Na₂SO₄), filtered, andconcentrated by rotary evaporation. Further drying at 0.6 mm Hg for 3 hgave a thick, light-brown oil (1.18 g). TLC analysis (CH₃OH-Et₃N,97.5:2.5, v/v) indicated the presence of(E)-N-methyl-N-(4-(3-aminophenyl)-3-buten-1-yl)benzamide (R_(f) 0.60)along with the desired product (R_(f) 0.19). Consequently, the crude oilwas treated with concentrated HCl (75 mL) and stirred and heated underreflux for 16 h. The mixture was cooled to 0° C., basified with 20% NaOHsolution (50 mL) to pH 12, and extracted with CHCl₃ (4×50 mL). Thecombined CHCl₃ extracts were washed with saturated NaCl solution (50mL), dried (Na₂SO₄), filtered, and concentrated by rotary evaporation.Further drying under high vacuum produced a brown oil (888 mg). TLCanalysis again indicated the presence of(E)-N-methyl-N-[4-(3-aminophenyl)-3-buten-1-yl]benzamide. Consequently,the crude material was treated with 20% sulfuric acid solution (50 mL)and stirred and heated under reflux at 135° C. (oil bath temperature)for 6 h. The resulting mixture was cooled to ambient temperature and wasfurther cooled to 0° C. A 20% NaOH solution (40 mL) was carefully added,with stirring, giving pH 12. The resulting mixture was extracted withCHCl₃ (5×40 mL). The combined CHCl₃ extracts were washed with saturatedNaCl solution (50 mL), dried (Na₂SO₄), filtered, and concentrated byrotary evaporation. Further drying under high vacuum produced adark-brown syrup (734 mg). The crude product was purified by columnchromatography on silica gel (50 g, 2.0 cm i.d. column) eluting withCH₃OH—Et₃N (97.5:2.5, v/v). Selected fractions containing the productwere combined and concentrated by rotary evaporation. The residue wasdissolved in CHCl₃, dried (Na₂SO₄), filtered, concentrated by rotaryevaporation, and further dried under high vacuum to give 241.3 mg(25.2%) of a light-brown oil. A portion (169.8 mg) of this material wasfurther purified by column chromatography on silica gel (25 g, 2.0 cmi.d. column) eluting with CH₃OH—Et₃N (97:3, v/v). Selected fractionscontaining the product (R_(f) 0.24 in CH₃OH—Et₃N (97:3, v/v)) werecombined and concentrated by rotary evaporation. The resulting yellowoil was dissolved in CHCl₃, dried (Na₂SO₄), filtered, concentrated byrotary evaporation, and further dried at 0.5 mm Hg for 3 h to give 130.6mg of a viscous, reddish brown oil.

Sample No. 2 exhibits a log P of 1.66, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The compound exhibits a Ki of 42 nM, indicatingthat the compound exhibits good binding to certain CNS nicotinicreceptors.

Sample No. 2 exhibits an EC₅₀ value of 913 nM and an E_(max) value of78% for dopamine release, indicating that the compound inducesneurotransmitter release thereby exhibiting known nicotinicpharmacology.

Sample No. 2 exhibits an E_(max) of 7% (at a concentration of 100 uM) atmuscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors to any significant degree. SampleNo. 2 exhibits an E_(max) of 3% (at a concentration of 100 uM) atganglionic-type receptors. The compound has the capability to activatehuman CNS receptors without activating muscle-type and ganglionic-typenicotinic acetylcholine receptors to any significant degree. Thus, thereis provided a therapeutic window for utilization in the treatment of CNSdisorders. That is, at certain levels the compound shows CNS effects toa significant degree but does not show undesirable muscle and ganglioneffects to any significant degree.

EXAMPLE 8

Sample No. 3 is (E)-N-methyl-5-(3-aminophenyl)-4-penten-2-amine, whichwas prepared in accordance with the following techniques:

N-(3-Bromophenyl)phthalimide

A stirring slurry of 3-bromoaniline (3.00 g, 17.44 mmol), phthalicanhydride (2.58 g, 17.44 mmol), and toluene (45 ml) was heated underreflux, using a Dean-Stark apparatus, at 140° C. (oil bath temperature)for 24 h. After cooling to ambient temperature, the solution wasconcentrated by rotary evaporation. The resulting off-white solid waspurified by column chromatography on silica gel (150 g, Merck 70-230mesh) eluting with CHCl₃-acetone (9:1, v/v) to collect unreacted3-bromoaniline (R_(f) 0.61) and phthalic anhydride (R_(f) 0.43). Elutionwith CHCl₃-methanol (9:1, v/v) gave the product (R_(f) 0.38). Selectedfractions containing the product were combined and concentrated byrotary evaporation to give 1.53 g of an off-white to light-beige solid.Impure fractions were combined and concentrated by rotary evaporation.The resulting white solid was dissolved in a mixture of CHCl₃, acetone,and methanol and re-chromatographed on silica gel (150 g). Elution withCHCl₃ removed impurities; the product was then eluted with CHCl₃-acetone(4:1, v/v). Selected fractions were combined, concentrated by rotaryevaporation, and vacuum dried for 16 h to give 1.41 g of an off-white tolight-beige solid, mp 176-179° C., bringing the total yield to 2.94 g(55.8%).

4-Penten-2-ol p-Toluenesulfonate

Under a nitrogen atmosphere, p-toluenesulfonyl chloride (16.92 g, 88.75mmol) was added to a cold (2° C.), stirring solution of 4-penten-2-ol(7.28 g, 84.52 mmol, Aldrich Chemical Company) in pyridine (60 mL). Thesolution was stirred at 2-5° C. for 2 h and allowed to warm to ambienttemperature over several hours. The mixture, containing white solids,was poured into cold 3 M HCl solution (250 mL) and extracted with CHCl₃(4×75 mL). The combined CHCl₃ extracts were washed with 3 M HCl solution(4×100 mL), saturated NaCl solution (2×50 mL), dried (Na₂SO₄), filtered,concentrated on a rotary evaporator, and further dried under high vacuumto afford 17.38 g (85.6%) of a light-amber oil.

N-Methyl-4-penten-2-amine

A 180-mL thick-walled glass pressure tube was charged with 4-penten-2-olp-toluenesulfonate (17.30 g, 71.99 mmol) followed by a 40% solution ofaqueous methylamine (111.85 g, 1.44 mol). The tube was sealed, and themixture was stirred and heated at 122° C. for 16 h and allowed to coolto ambient temperature. After further cooling to 0-5° C., thelight-yellow solution was saturated with solid NaCl and extracted withdiethyl ether (6×40 mL, inhibitor-free). The combined light-yellow etherextracts were dried (Na₂SO₄) and filtered. The ether was removed bydistillation at atmospheric pressure using a 6-inch Vigreaux column anda short-path distillation apparatus. The residual light-yellow oil wasdistilled at atmospheric pressure collecting 3.72 g (52.1%) of acolorless oil, bp 75-105° C.

N-Methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine

Di-tert-butyl dicarbonate (6.84 g, 31.35 mmol) was quickly added inseveral portions to a cold (0-5° C.), stirring solution ofN-methyl-4-penten-2-amine (3.66 g, 25.68 mmol) in dry tetrahydrofuran(25 mL, freshly distilled from sodium and benzophenone). The resultinglight-yellow solution was stirred and allowed to warm to ambienttemperature over several hours. The solution was concentrated on arotary evaporator. The resulting oil was vacuum distilled using ashort-path distillation apparatus, collecting 5.22 g (88.4%) of analmost colorless oil, bp 85-86° C. at 5.5 mm Hg.

(E)-N-Methyl-N-(tert-butoxycarbonyl)-5-[(1-N-phthaloyl)-3-phenyl]-4-penten-2-amine

A 180-mL thick-walled glass pressure tube was charged with a mixture ofN-(3-bromophenyl)phthalimide (1.94 g, 6.43 mmol), palladium(II) acetate(14.4 mg, 0.06 mmol), tri-o-tolylphosphine (78.3 mg, 0.26 mmol),triethylamine (4 mL, 28.70 mmol),N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.28 g, 6.43 mmol),and acetonitrile (6 mL). The tube was flushed with nitrogen and sealed.The mixture was stirred and heated at 115° C. (oil bath temperature) for112 h. After cooling to ambient temperature, the resulting solid residuewas diluted with water (20 mL) and extracted with CH₂Cl₂ (4×20 mL). Thecombined CH₂Cl₂ extracts were washed with a saturated NaCl solution (30mL), dried (Na₂SO₄), filtered, concentrated by rotary evaporation, andvacuum dried to give a viscous oil (3.00 g). The crude product waspurified by column chromatography on silica gel (120 g, Merck 70-230mesh) eluting with ethyl acetate-hexane (1:1, v/v). Selected fractionscontaining the product (R_(f) 0.44) were combined, concentrated byrotary evaporation, and vacuum dried to give 1.01 g (37.3%) of aviscous, light-yellow oil.

(E)-N-Methyl-5-(3-aminophenyl)-4-penten-2-amine

Under a nitrogen atmosphere, a stirring ice-cold (0-5° C.) solution of(E)-N-methyl-N-(tert-butoxycarbonyl)-5-[(1-N-phthaloyl)-3-phenyl]-4-penten-2-amine(1.01 g, 2.40 mmol) in anisole (13 mL) was treated dropwise over 10 minwith trifluoroacetic acid (16.28 g, 142.8 mmol). After stirring at 0-5°C. for 45 min, the solution was concentrated by rotary evaporation, andthe residue was further dried under vacuum. The resulting yellow syrupwas treated with a 25% (w/w) solution of methylamine in ethanol (50 mL)and allowed to stir for 48 h. The mixture was concentrated on a rotaryevaporator. The resulting residue was diluted with water (20 mL),treated with saturated NaCl solution (25 mL), and basified to pH 10 with10% NaOH solution. The mixture was extracted with CHCl₃ (6×30 mL). Thecombined CHCl₃ extracts were dried (Na₂SO₄), filtered, and concentratedby rotary evaporation to produce a light-yellow oil (0.52 g). The crudeproduct was purified by column chromatography on silica gel (Merck70-230 mesh) eluting with CHCl₃—CH₃OH (1:1, v/v, containing 2% (v/v)Et₃N). Selected fractions were combined and concentrated by rotaryevaporation to give a light-yellow oil (0.271 g). The oil was furtherpurified by column chromatography on silica gel containing 5 wt % silvernitrate (30 g, silica gel 60, Merck 9385) eluting with CH₃OH—Et₃N (9:1,v/v). Selected fractions containing the product (R_(f) 0.39) werecombined and concentrated by rotary evaporation. The resulting brown oilwas filtered through silica gel (12.5 g, Merck 70-230 mesh) eluting withCH₃OH—Et₃N (9:1, v/v). The filtrate was concentrated by rotaryevaporation. The resulting yellow oil was dissolved in CHCl₃, dried(MgSO₄), filtered, concentrated by rotary evaporation, and further driedunder vacuum to give 0.15 g (32.7%) of a yellow oil.

Sample No. 3 exhibits a log P of 2.07, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The compound exhibits a Ki of 132 nM. The lowbinding constant indicates that the compound exhibits good high affinitybinding to certain CNS nicotinic receptors.

Sample No. 3 exhibits an EC₅₀ value of 920 nM and an E_(max) value of78% for dopamine release, indicating that the compound effectivelyinduces neurotransmitter release thereby exhibiting known nicotinicpharmacology.

Sample No. 3 exhibits an E_(max) of 2% (at a concentration of 100 uM) atmuscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of6% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but does not show undesirable muscle or ganglioneffects to any significant degree.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein.

That which is claimed is:
 1. A compound having the formula:

where A^(IV) is OR″ or NO₂; A, A^(I), A^(II) and A^(III) are substituentspecies characterized as having a sigma m value between about −0.3 andabout 0.75; E^(I), E^(II), E^(III), R′, R″, Z and Z^(I) are individuallyhydrogen or lower alkyl; n is an integer from 1 to 5; and the wavy linein the structure indicates that the compound can have the cis (Z) ortans (E) form.
 2. The compound of claim 1 wherein the compound has atrans (E) form, R′ and R″ both are hydrogen, E^(I) and E^(II) each arehydrogen, E^(III) is hydrogen or lower alkyl, Z is hydrogen or methyl,and Z, is hydrogen.
 3. The compound of claim 1 wherein n is 1 or
 2. 4. Apharmaceutical composition incorporating a compound having the formula:

where A^(IV) is OR″ or NO₂; A, A^(I), A^(II) and A^(III) are substituentspecies characterized as having a sigma m value between about −0.3 andabout 0.75; E^(I), E^(II), E^(III), R′, R″, Z and Z^(I) are individuallyhydrogen or lower alkyl; n is an integer from 1 to 5; and the wavy linein the structure indicates that the compound can have the cis (Z) ortans (E) form.
 5. The pharmaceutical composition of claim 4 wherein thecompound has a trans (E) form, R′ and R″ both are hydrogen, E^(I) andE^(II) each are hydrogen, E^(III) is hydrogen or lower alkyl, Z ishydrogen or methyl, and Z^(I) is hydrogen.
 6. The pharmaceuticalcomposition of claim 1 wherein n is 1 or
 2. 7. A method for treating acentral nervous system disorder characterized by an alteration in normalneurotransmitter release comprising administering to a subject in needthereof, an effective amount of a compound of the formula:

where A^(IV) is OR″ or NO₂; A, A^(I), A^(II) and A^(III) are substituentspecies characterized as having a sigma m value between about −0.3 andabout 0.75; E^(I), E^(II), E^(III), R′, R″, Z and Z^(I) are individuallyhydrogen or lower alkyl; n is an integer from 1 to 5; and the wavy linein the structure indicates that the compound can have the cis (Z) ortans (E) form.
 8. The method of claim 7 whereby the compound has a trans(E) form, R′ and R″ both are hydrogen, E^(I) and E^(II) each arehydrogen, E^(III) is hydrogen or lower alkyl, Z is hydrogen or methyl,and Z^(I) is hydrogen.
 9. The method of claim 7 whereby n is 1 or 2.